WO2024224355A1

WO2024224355A1 - A low dose formulation of l-serine for liver health and fatty liver diseases

Info

Publication number: WO2024224355A1
Application number: PCT/IB2024/054089
Authority: WO
Inventors: Hemanshu MUNDHADA; Nielsen Alex TOFTGAARD; Varun SUREJA; Dharmeshkumar KHENI; Geet Arora
Original assignee: Cysbio Aps
Priority date: 2023-04-26
Filing date: 2024-04-26
Publication date: 2024-10-31

Abstract

The present invention relates to a low dose formulation of L-serine for liver health and fatty liver diseases. More particularly, the present invention provides a formulation of L-serine for which the daily dose is between 2 and 15 g per person per day. The claimed formulations are efficacious and useful for fatty liver disease patients and individuals at risk of developing a fatty liver disease including individuals with elevated liver fat levels. Furthermore, the present invention provides novel efficient methods of use of such formulations.

Description

A LOW DOSE FORMULATION OF L-SERINE FOR LIVER HEALTH AND FATTY LIVER DISEASES FIELD OF THE INVENTION The present invention provides novel formulations for supporting or stimulating lipid metabolism and/or liver health. More particularly, the present invention provides a low dose formulation of L-serine for supporting or stimulating lipid metabolism and/or liver health. More particularly, the present invention provides a formulation of L-serine for which the recommended daily dose is between 2 and 15 g per person. The claimed formulations are efficacious and useful for fatty liver disease patients, and individuals at risk of developing a fatty liver disease including individuals with elevated liver fat levels. Furthermore, the invention is useful in that it provides highly affordable, organoleptically acceptable, stable, and tolerable formulations. Embodiments of the invention include, but are not limited to, L-Serine containing dietary supplement; L-Serine containing dietary ingredient; L-Serine containing food ingredient; L-Serine containing food additive; L-Serine containing functional food or nutraceutical; and L-Serine containing drug, -pharmaceutical, -medical, or - prescription medicine for supporting or stimulating lipid metabolism and/or liver health. Furthermore, the present invention provides novel efficient methods of use of such formulations. BACKGROUND OF THE INVENTION Liver and brain are the largest human organs, underlining their key cognitive and metabolic roles, respectively. The liver can be considered the metabolic motor of the body. With modern lifestyle, liver disorders, and fatty liver diseases especially, constitute a silent worldwide epidemic i.e. an increasingly prevalent, under-addressed complex of diseases and conditions with an urgent need of diagnostic and therapeutic solutions¹. The liver has multiple life-supporting functions like defense against infections, production of bile, digestion of most of the nutrients absorbed by the intestine, conversion of nutrients into energy, storage of iron, production of proteins, detoxifying blood, and producing factors needed for blood clotting. The liver, most importantly, stores, releases, and recycles potential energy. The accelerated metabolic demands of the working muscle cannot be met without a robust response from the liver. If not for the liver/hepatic response, sustained exercise would be impossible. Exercise would result in hypoglycemia if it were not for the accelerated release of energy as glucose. The energetic demands on the liver are largely met by increased oxidation of fatty acids mobilized from fat tissue. Lipids are a major class of biochemical compounds that includes oils as well as fats. Organisms use lipids to store energy and for many other uses. Lipid molecules consist mainly of repeating units called fatty acids. The liver is the central organ for fatty acid metabolism. Fatty acids accrue in liver by uptake from the plasma and by de novo biosynthesis. Fatty acids are eliminated by oxidation within the cell or by secretion into the plasma within triglyceride-rich very low- density lipoproteins. Steatosis is abnormal retention of fat (lipids) within a cell or organ. Steatosis most often affects the liver where the condition is commonly referred to as fatty liver disease. Steatosis reflects an impairment of the normal processes of synthesis and elimination of triglyceride fat i.e. impairment of normal lipid metabolism. Fatty liver disease is therefore a condition in which excess fat builds up in the liver. There are two main types of fatty liver disease: Nonalcoholic fatty liver disease and alcoholic fatty liver disease. A healthy liver contains a small amount of fat, typically up to approximately 5% dependent on the population and method of quantification (see methods below). It becomes a pathological condition when the fat content of the liver exceeds approximately 5% of the liver’s weight. Alcoholic fatty liver disease is caused by heavy alcohol use. The liver breaks down most of the alcohol consumed by a person, so it can be removed from the body. But the process of breaking it down can generate harmful substances. These substances can damage liver cells, promote inflammation, and weaken the body's natural defenses. Alcoholic fatty liver disease is the earliest stage of alcohol- related liver disease. The next stages include alcoholic hepatitis and cirrhosis. Nonalcoholic fatty liver disease (NAFLD) is the most common liver disorder worldwide, regularly coexisting with metabolic disorders such as type 2 diabetes, hypertension, obesity, and cardiovascular disease, and is frequently recognized as the liver manifestation of metabolic syndrome. It seems that total calorie consumption, rather than dietary fat composition, is an important factor in the development of fatty liver disease in humans². Eating excess calories causes fat to build up in the liver. NAFLD – or hepatic steatosis - occurs when intrahepatic fat content exceeds 5% of liver weight. NAFLD as defined here includes the recently proposed metabolic-associated fatty liver disease (MAFLD)³. NAFLD progresses to nonalcoholic steatohepatitis (NASH) when it is accompanied by inflammation of the liver. NASH may eventually progress to cirrhosis, liver cancer, and liver failure. A recent systematic review and meta-analysis based on 72 publications with a sample population of more than 1 million individuals from 17 countries showed that worldwide prevalence of NAFLD is increasing at an alarming rate⁴. It estimates the global prevalence of NAFLD to have risen from 25% of the population in 2005 to 32% of the population in 2016 or later. However, since diagnosis of the disease requires a liver biopsy, the disease is severely under diagnosed. Other reports estimate that NAFLD is present in approximately 25% of the world's population. It is very common in western countries. In the United States, it is the most common form of chronic liver disease, affecting about one- quarter of the population. With the possible development of new non-invasive diagnostic methods more accurate prevalence estimates should follow. NAFLD is now the second most common cause of chronic liver disease among individuals listed for liver transplantation in the USA. The increasing prevalence of obesity and the metabolic syndromes is leading to an increased incidence of NAFLD. The increasing prevalence of NAFLD is especially worrying because previous and recent data have shown that mortality is higher in NAFLD as compared to AFLD. The prevalence of NAFLD in the general population increases with age; from 1 to 3% in children, 5% in teenagers, 18% between 20 and 40 years, 39% in those aged 40 to 50 years, and to over 40% in those older than 70 years. Worldwide prevalence of NAFLD is considerably higher among men than woman. Greater awareness of NAFLD and the development of cost-effective risk stratification strategies are warranted to address the growing burden of NAFLD and accompanying health issues and diseases. Risk stratification enables providers to identify the right level of care and services for distinct subgroups of a population of patients or individuals, including individuals at risk of developing disease. It is the process of assigning a risk status to individuals or populations, then using this information to direct care and improve overall health outcomes. Individuals in risk of developing fatty liver disease include metabolic syndrome patients, type 2 diabetes mellitus patients, obesity patients (BMI>30), elderly and individuals with elevated liver fat level⁵. In spite of the very high prevalence of the disease, currently, no medical treatment exists for NAFLD or some of the important accompanying conditions. Diet and physical exercise are the recommended non-pharmacological measures which have to be tailored individually. Diet and exercise can slow the progression of disease, lessen or prevent symptoms, help maintain liver values, manage other issues e.g. diabetes, high blood pressure and cardiovascular disease and contribute to overall health. However, it is well established that for a number of reasons diet and exercise alone are unlikely to halt or reverse the ongoing metabolic/lifestyle crisis. The continuously increasing prevalence of NAFLD and accompanying conditions underlines the strong need for additional or alternative measures, including medical and non-medical measures. The proper therapeutic methods will also have to consider the peculiarities of the target individual/population and multidisciplinary approaches may be mandatory e.g. in geriatric patients. E.g. non-pharmacological treatment (diet and physical exercise) has to be tailored individually considering the physical limitations of most elderly people and the need for an adequate caloric supply. Similarly, the choice of drug treatment must carefully balance the benefits and risks in terms of adverse events and pharmacological interactions in the common context of both multiple health conditions and polypharmacy. Therefore, there is a need for both pharmacological and non-phamacological interventions. Liver health indicators and early-stage diagnosis using non-invasive methods will be key in developing and broadly implementing stratification and prevention/treatment regimes. Screening/diagnosis using ultra-sound technology is a promising technology which may be one such key method⁶, which may allow earlier diagnosis and identification of individuals at risk of developing NAFLD allowing to start preventive measures pre-symptomatically. MRI-PDFF is another promising method⁷. The fatty liver index (FLI) is an algorithm based on waist circumference, body mass index (BMI), triglyceride, and gamma-glutamyl-transferase (GGT) for the prediction of fatty liver.⁸ FLI = (e ^{0.953×loge(triglycerides)}

0^{.053×waist circumference − 15.745}) /

^{0.953×loge (triglycerides)}

100 Liver function tests are tests that measure different substances giving important information about the overall liver health. Often, several substances are measured in one blood sample. It may include various enzymes, proteins and by-products. Common liver function tests include: ^ Liver enzymes test. Including alkaline phosphatase (ALP), alanine transaminase (ALT), aspartate aminotransferase (AST) and gamma- glutamyl transferase (GGT) test. These enzyme levels are elevated when there’s liver injury. ^ Total protein test. A total protein test measures levels of protein in your blood. Low protein levels may indicate that the liver isn’t functioning optimally. ^ Bilirubin test. Bilirubin is a waste product that the liver deposits in bile. ^ Prothrombin time (PT) test. This test measures how long it takes for a blood sample to clot, a process that involves proteins that the liver produces. Lipid profile test measures total Cholesterol, HDL, LDL, TG, and Apo-B. Normal liver function test value ranges vary between different sexes and body sizes, as well as between different laboratories. On average, normal ranges are: ^ Alanine transaminase (ALT): 0 to 45 IU/L. ^ Aspartate transaminase (AST): 0 to 35 IU/L. ^ Alkaline phosphatase (ALP): 30 to 120 IU/L. ^ Gamma-glutamyltransferase (GGT): 0 to 30 IU/L. ^ Bilirubin: 2 to 17 micromoles/L. ^ Prothrombin time (PT): 10.9 to 12.5 seconds. ^ Albumin: 40 to 60 g/L. ^ Total proteins: 3 to 8.0 g/dL. In summary, in spite of increasingly overwhelming evidence of a fast growing metabolic, lipid metabolism and liver health crisis over the past decades, there is an urgent need for diagnostic methods, medical and non-medical solutions and therapeutic methods for non-patients and patients alike to support or stimulate liver health and/or lipid metabolism, including treating and/or preventing liver diseases including AFLD, NAFLD and prevent further progression to e.g. NASH, cirrhosis, liver cancer and liver failure. L-Serine is an amino acid which has wide application in pharma and cosmetic industry. L-serine in the form of pills/tablets/capsules in small dosages (up to 500 mg pr dose and pr day pr person) are used as a dietary supplement for better sleep and cognitive functions⁹. High doses of L-Serine (20 to 30 g/day) are in Phase three clinical trials for neurodegenerative diseases¹⁰. In recent studies L-Serine has been studied in alcohol induced fatty liver disease in mouse models¹¹. The doses of L-serine studied were 20 mg/kg and 200 mg/kg which is equivalent to 1.62 mg/kg and 16.2 mg/kg human equivalent dose (HED) respectively which corresponds to 162 mg to 1.62 g/ day for an adult weighing close to 100 Kg. However clinical trials on low L-serine dosage studies on humans are missing. On the contrary, there are human clinical trials available which utilize more than 20 gm/day dose of L-serine including a phase 1 and 2 clinical trial, NCT02599038 for “Serine Supplementation for Obese Subjects with Fatty Liver Disease” which utilizes 0.2g/kg/day of L-serine¹². However, the results of these trials are not available. Additional studies with Clinical data of L-serine in high dosages in combination with N-acetylcysteine, Carnitine and Nicotinamide riboside are available ^13,14. In these trials L-serine was included in the combination at more than 20 g/day, whereas L-Serine alone was not tested. In summary, current state of the art teaches that L-Serine as a dietary supplement in up to 500 mg/day/person supports sleep, cognitive and other positive neurological effects. On the other hand, L-serine as a drug in 20-30 g/day/person supports positive clinical effects on patients with neurodegenerative diseases. Finally, clinical trials support that a drug consisting of a combination of metabolic co-factors including L-serine (20-30 g/day/person), L-carnitine, N-acetylcysteine, and nicotinamide riboside may significantly improve liver health indicators of NAFLD patients. N-acetylcysteine, one key active ingredient in prior art combination of metabolic co-factors to improve liver health – like many other sulfur-containing compounds - suffers from poor organoleptic properties such as a strong sulfur smell, a bitter aftertaste, and astringency. These poor organoleptic properties are very difficult to mask not least in the amounts described for this use to improve liver health indicators. Dandoy et al. e.g. conclude that N-acetylsysteine diluted with Fresca™ to a 5% solution had the least offensive odor and taste and should be considered as an option when administering oral N-acetylcysteine to adults¹⁵. Therefore, to increase the likelihood of product use and adoption there is a need for a solution for stimulating liver health not containing N-acetylcysteine, especially when/if it is recommended to take on a regular basis e.g. on a daily basis and/or more than once daily. It has previously been shown that L-Serine by the use of metabolic engineering can be produced highly efficiently¹⁶. This makes L-Serine prone to inclusion even in gram amounts as an ingredient in highly affordable solutions. Finally, it can be desirable to provide a mono-ingredient formulation allowing optimization of formulation and use to the specific properties of the single active ingredient. OBJECTIVE OF THE INVENTION The main objective of the present invention is to provide an affordable, organoleptically acceptable, efficacious and tolerable oral formulation for supporting or stimulating lipid metabolism and/or liver health in fatty liver disease patients and non-patients alike, including in individuals at risk of developing a fatty liver disease e.g. individuals with elevated liver fat levels. Another objective of the present invention is to provide an effective method of use of said formulation. A further objective of the present invention is to provide new tools (formulations and methods) to enable further stratification of populations and solutions for stimulation of liver health. SUMMARY OF THE PRESENT INVENTION The inventors of the present invention have surprisingly found that dietary supplementation with a low dose of L-serine (2-15 g/person/day) can support or stimulate lipid metabolism and/or liver health both in fatty liver disease patients and in non-patients, including individuals at risk of developing a fatty liver disease, e.g. individuals with elevated liver fat levels. The dosage of L-serine in the range of 2 g to 15 g per day corresponds to between 0.025 g/Kg/day to 0.18 g/Kg/day assuming the average weight of patients around 85 Kg. This dose range is higher than human equivalent dose estimated from mouse model studies and lower than used and/or demonstrated efficacious in human clinical studies. L-Serine at low dose fulfills all the requirements for an active ingredient candidate for regularly repeated use: it is tolerable, organoleptically acceptable, stable and readily mixable and therefore very versatile as an ingredient for formulation, and since it can be used as the only active ingredient, efficacy of such formulations with L-Serine can be more readily optimized in accordance with the properties (organoleptic-, pharmacokinetic- or other properties) of L-Serine specifically. The main aspect of the present invention is thus to provide a low dose L-serine formulation for supporting or stimulating lipid metabolism and/or liver health. A preferred embodiment of the present invention pertains to a low dose L-serine formulation for supporting or stimulating lipid metabolism and/or liver health comprising L-serine as the only active ingredient. In a further preferred embodiment, the low dose L-serine formulation comprises excipients improving its organoleptic properties. In a further preferred embodiment, the L-serine formulation according to the current invention can be in the form of a dietary supplement (e.g. powder, liquid or tablet), a dietary ingredient, a food ingredient or food additive, a food, a functional food or nutraceutical, a medication, pharmaceutical, drug or prescription medicine. In one preferred embodiment the formulation of the present invention is for use by fatty liver patients. In another preferred embodiment the formulation of the present invention is for use by non-patients, including individuals at risk of developing a fatty liver disease, e.g. individuals with elevated liver fat levels. Another aspect of the present invention is novel efficient methods of use of formulations of the present invention. A preferred embodiment pertains to novel efficient methods of use of formulations of the present invention comprising twice or more daily oral intake, each preferably in connection with a meal. DETAILED DESCRIPTION OF THE INVENTION The detailed description set forth below is intended as a description of exemplary embodiments and is not intended to represent the only forms in which the exemplary embodiments may be constructed and/or utilized. The description sets forth the functions and the sequence of steps for constructing and/or operating the exemplary embodiments. However, it is to be understood that the same or equivalent functions and sequences which may be accomplished by different exemplary methods are also intended to be encompassed within the spirit and scope of the invention. As defined herein, all scientific and technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the invention belongs, unless specifically defined otherwise herein. Although any process and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are now described. As stated in the present invention herein, the singular forms “a,” “an” and “the” specifically also encompass the plural forms of the terms to which they refer, just as the plural forms specifically also encompass the singular forms, both unless the content clearly dictates otherwise. The term “about” is used herein to means approximately, in the region of, roughly, or around. As stated herein, that it follows in a transitional phrase or in the body of a claim, the terms “comprise(s)” and “comprising” are to be interpreted as having an open ended meaning. That is, the terms are to be interpreted synonymously with the phrases “having at least” or “including at least”. When used in the context of a process, the term “comprising” means that the process includes at least the recited steps, but may include additional steps. When used in the context of a composition, the term “comprising” means that the composition includes at least the recited features or components, but may also include additional features or components. The term “fatty liver disease” used herein refers to a disease condition caused by having too much fat build up in the liver. There are two main forms of fatty liver disease: Alcohol-induced fatty liver disease and Non-alcoholic fatty liver disease. The word fatty liver used herein is applicable to both forms as well as any further progressed form e.g. NASH, cirrhosis, and liver cancer. The term “individual at risk of developing a fatty liver disease” used herein refers to individuals who do not have a fatty liver disease diagnose, i.e. “non-patients” with an increased risk of developing a fatty liver disease, including, without limitation, metabolic syndrome patients, type 2 diabetes mellitus patients, obesity patients (BMI>30), elderly, and individuals with elevated liver fat levels. The term “elevated liver fat levels” used herein refers to liver fat levels above the norm for healthy individuals. This can be measured by one of several means including liver biopsy, fatty liver index, MRI-PDFF and ultrasound. The term “L-serine” can be interchangeably used as “L-serine” and “serine”. The term “formulation” used herein refers to any formulation i.e. active ingredient alone or in combination with other ingredient(s) for oral ingestion. Examples of formulations include without limitation dietary supplements, dietary ingredients, food, food ingredient, food additive, functional food, nutraceutical, medication, pharmaceutical, drug or prescription medicine. The term “active ingredient” used herein refers to any ingredient with a nutritional and/or health purpose, as opposed to ingredients with a different purpose e.g. of acting as excipients e.g. fillers, binders, coatings, disintegrants, prservants, texturizers, colors, flavors, acidifiers, sweeteners etc.. The term “dietary supplement” used herein refers to a product intended for ingestion that contains a dietary ingredient intended to supplement the diet. Dietary supplements may be found in many forms including, but not limited to, powders, liquids, pills, tablets, effervescent tablets, capsules, gummies, and soft gels. Dietary supplements can also be in the same form as a conventional food category, such as teas or bars, but only if the product is not represented as a conventional food or as a sole item of a meal or the diet. Dietary supplements may be single-ingredient or multiple-ingredient supplements. In this case, the prefix single- or multiple- refers to the number of ingredients with a nutritional and/or health purpose (also referred to as “active ingredient”) as opposed to ingredients with the purpose of acting as excipients, fillers, texturizers, colors, flavors etc. The term “dietary ingredient” used herein refers to a product intended as ingredient for the production of a product for oral ingestion, including, but not limited to, amino acids; proteins; vitamins and minerals; herbs and other botanicals; dietary substances that are part of the food supply, such as enzymes and live microbials (commonly referred to as probiotics); and concentrates, metabolites, constituents, extracts, or combinations of any dietary ingredient. The term “food” used herein refers to any substance consumed by human beings for nutritional support. Examples of foods include, but are not limited to: processed foods, drinks, beverages, dairy products, and baked goods. The terms “food ingredient” or “food additive” are used interchangeable herein to refer to any substance the intended use of which results in becoming a component and/or otherwise affecting the characteristics of any food. Examples of food ingredients and additives include, but are not limited to: flours, powders, liquids, juices, mineral drinks, milks. The terms “functional food” or “nutraceutical” are used interchangeably herein. Functional foods beneficially affect one or more target functions in the body - beyond the effects of providing generally recognized essential nutrients - in a way that is relevant to either an improved state of health and wellbeing and/or reduction in risk of disease, without being a prescription medicine. Such foods are also called fortified, enriched or enhanced foods. The terms “medication”, “pharmaceutical”, “drug” or “prescription medicine” are used interchangeably herein. They refer to a product or ingredient that is intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of human disease or to affect the structure or any function of the human body, and which for acquisition, use or consumption requires prescription from authorized medical personnel. For the purpose of this invention, the term “oral formulation” shall mean any formulation for oral ingestion by a human, including, without limitation, dietary supplement, dietary ingredient, food, food ingredient, food additive, functional food, nutraceutical, and/or medication, drug etc. This shall include formulations which are further handled prior to oral ingestion, e.g. by dissolution in liquid or by other means The terms "liver health indicators”, “liver values”, and “liver function tests” are used interchangeable herein referring to parameters correlated with liver function, which includes liver fat levels. Some typical liver function tests are described in “Background of the invention” hereto, but are not limited thereto. Excipient shall mean an ingredient which is not an active ingredient. The term “non-patient” used herein refers to any individual without a fatty liver disease diagnose. The term “nutraceutical” used herein refers to any substance used to promote general well-being, control symptoms, and prevent malignant processes. It is a pharmaceutical alternative which claims physiological benefits which can be consumed by normal person or person suffering for any disease as dietary supplements or nutritional supplement. The terms “efficacy” and “efficacious” used herein refer to the ability of a formulation to produce or achieve the desired therapeutic effect. The terms “efficiency” and “effective” used herein refer to the ability of a method to produce or achieve the desired therapeutic effect. The term “recommended daily dose” and “recommended dose” and “daily dose” used herein refer to a product and/or target group specific recommended dose as typically provided together with a commercial product, as opposed to – and not to be confused with – the recommended daily allowance and/or daily value which are generic guidelines and/or recommendations applying to most healthy people. The term “subject” used herein refers to an individual who participates in a clinical trial either as a recipient of the investigational product(s) or as a control. The term “subject” may be used interchangeably with “participant”. The term “supporting or stimulating lipid metabolism and/or liver health” used herein refers to improving liver function test values, liver values or liver fat levels The term “therapeutic effect” used herein refers to the response(s) after a use of any kind on an individual or a population of individuals, the results of which are judged to be useful or favourable. Similarly, such use is interchangeably termed “therapeutic use” or “therapeutic method”. The term “bulking agent” used herein refers to agents which are required to provide a matrix to carry the drug which are normally present in low quantities. The term “diluent” used herein refers to agents which are responsible for increasing the weight, volume, or dosage form in a nutraceutical product. They are also known as filers, The term “Acidity regulator” used herein refers to chemical compounds that give a tart, sour, or acidic flavor to foods or enhance the perceived sweetness of foods. They are also known as “acidifier”. The low dose of L-serine mentioned in the whole specification including claims should be considered as mg/kg body weight of a person per day. The average body weight of a person need to be considered 75 kg-77 kg. The main embodiment of the present invention is to provide a low dose formulation of L-serine for liver health and fatty liver diseases. One embodiment of the present invention pertains to a low dose formulation of L- serine for liver health and fatty liver diseases comprising L-serine as the only active ingredient. As per one embodiment, a low dose formulation of L-serine for liver health and fatty liver diseases for which the daily dose of L-Serine is between 25mg/kg and 200 mg/kg body weight of a person. As per one embodiment, the low dose formulation of L-serine for liver health and fatty liver diseases comprising the daily dose of L-Serine is between 25mg/kg and 200mg/kg body weight of a person, more preferably 50mg/kg and 160mg/kg of body weight of a person, more preferably 40mg/kg and 150mg/kg of body weight of a person, and most preferably 50mg/kg and 130mg/kg body weight of a person, and most preferably 64mg/kg and 127mg/kg body weight of a person. In a preferred embodiment, the low dose L-serine formulation comprises excipients improving its organoleptic properties. In more preferred embodiment, a low dose formulation of L-serine for liver health and fatty liver diseases further comprising bulking agent, diluent, acidity regulator and one or more excipients. As per one embodiment, said bulking agent is selected from the group consisting of isomalt, lactitol, maltitol, mannitol, sorbitol, xylitol, lactose sucrose, dextran, and trehalose. As per one embodiment, the said bulking agent is used in the range of 0.83% w/w -16.66% w/w, preferably 1.66% w/w-16.66% w/w, more preferably 1.66% w/w - 13.33% w/w, and most preferably 1.66% w/w-8.33% w/w. As per one embodiment, said diluent diluent is selected from the group consisting of calcium carbonate, kaolin, sorbitol, maltodextrin, lactose, lactitol, maltose, and mannitol. As per one embodiment, the said diluent is used in the range 0.83% w/w -16.66% w/w, preferably 1.66% w/w-16.66% w/w, more preferably 1.66% w/w -13.33% w/w, and most preferably 1.66% w/w-8.33% w/w. As per one embodiment, said acidity regulator is selected from the group consisting of fumaric acid, malic acid, citric acid, ascorbic acid, tartaric acid, lactic acid, and calcium acetate. As per one embodiment, said acidity regulator is used in the range 0.016% w/w- 1.66% w/w, preferably 0.16% w/w-1.66% w/w, more preferably 0.83% w/w-1.5 %w/w and most preferably 1-1.5% w/w. As per one embodiment, the low dose formulation of L-serine for liver health and fatty liver diseases, comprises one or more excipients being a flavour an sweetener, glidant, preservative or combinations thereof. As per one embodiment, the said the one or more excipient are one or more of the following: lemon flavor, orange flavor, xylitol, maltitol, sorbitol, polyglycitol, steviol glycoside, sodium propionate, sodium benzoate, benzoic acid, talc, magnesium stearate, stearic acid. As per preferred embodiment, the said one or more excipient are one or more of the following: lemon flavor, steviol glycoside, magnesium stearate, and sodium benzoate. In a further preferred embodiment, the L-serine formulation according to the current invention can be in the form of a dietary supplement (e.g. powder, liquid or tablet), a dietary ingredient, a food ingredient or food additive, a food, a functional food or nutraceutical, a medication, pharmaceutical, drug or prescription medicine. In one preferred embodiment the formulation of the present invention it is for use by fatty liver patients for treatment of a fatty liver disease. In one preferred embodiment the formulation of the present invention it is used in the treatment of NAFLD. In another preferred embodiment the formulation of the present invention is for use by non-patients, including individuals at risk of developing a fatty liver disease, e.g. individuals with elevated liver fat levels. Another main embodiment of the present invention is novel efficient methods of use of formulations of the present invention. A preferred embodiment pertains to novel efficient methods of use of formulations of the present invention comprising once or twice or more daily oral intake, each preferably in connection with a meal. The invention is further illustrated by the following examples which are provided to be exemplary of the invention and do not limit the scope of the invention. While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention. EXAMPLES EXAMPLE 1: L-SERINE FORMULATION WITH MASKING AGENT Sr. Ingredients Role Qty. (mg) Qty (%w/w) No. per sachet per sachet 1 L-Serine Active Ingredient 5000 83.33 2 Maltodextrin Diuent 404 6.73 3 Isomalt Bulking agent 354 5.9 4 Powderome Lemon Flavouring agent 140 2.33 premium 5 Citric acid Acid regulator 80 1.33 6 Steviol glycoside Sweetening agent 16 0.26 7 Magnesium stearate Glidant 4 0.06 8 Sodium benzoate Preservative 2 0.03 Total weight: 6 gm Table 1: L-Serine formula composition details Sr. Ingredients Qty. (mg) Qty (%w/w) No. per sachet per sachet 1 Maltodextrin 404 6.73 2 Isomalt 5354 89.23 3 Powderome Lemon premium 140 2.33 4 Citric acid 80 1.33 5 Steviol glycoside 16 0.26 6 Magnesium stearate 4 0.06 7 Sodium benzoate 2 0.03 Total weight: 6 gm Table 2: Placebo formula composition details The patients were asked to dissolve it in 1 glass of water and drink it after their meals (breakfast, lunch and dinner). To follow double blind placebo-controlled trials, each patient should get equal number of sachets so that it was not disclosed to doctors as well. This however means that 5 g / 5000 mg and 10 g / 10000 mg contains 1 and 2 sachets of placebo each. EXAMPLE 2: CLINICAL STUDY 2.1: Enrolment of subjects and studied parameters a randomized, double blind, placebo controlled, dose ranging, parallel group study was conducted to evaluate safety/tolerability and the efficacy of amino acid supplementation to improve liver function in subjects with Non- Alcoholic Fatty Liver Disease (NAFLD). The study consists of 4 visits as described below. • Visit 1: Screening, Enrolment & Randomization Visit (Day -5 to 1) • Visit 2: Follow up visit: Day 28 (±2 days) • Visit 3: Follow up visit: Day 56 (±2 days) • Visit 4: End of study visit: Day 84 (±2 days) On the day of enrolment & randomization visit, all subjects were dispensed with subject diary and investigational product with instruction of its consumption as described below. • Grp 1: 3 Placebo sachets • Grp 2: Supplement Mix- 1 sachet + 2 Placebo sachets • Grp 3: Supplement Mix- 2 sachets + 1 Placebo sachet 2.2: Selection of Study Population Subject selection for the study was done based on the following inclusion and exclusion criteria. Subjects were eligible for enrolment into the study, if they met all of the inclusion criteria and none of the exclusion criteria. A. Inclusion criteria 1. Male or female subjects between 20-50 years of age (both inclusive) with Non-Alcoholic fatty Liver Disease (Grade I & II). 2. Subject has provided written, signed and dated informed consent to participate in the study. 3. Subject was willing and able to comply with the protocol. B. Exclusion criteria 1. Subject is participating in another clinical trial or has received an investigational product within thirty days prior to enrolment. 2. Subject has a history of alcohol or other drug abuse in the past year. 3. Subject has a known allergy or sensitivity to any ingredient in the test product. 4. Subject has any medical condition or uses any medication, nutritional product, dietary supplement or program, which in the opinion of the investigator, might interfere with the conduct of the study or place the subject at risk. 5. Investigator is uncertain about subject’s capability or willingness to comply with the protocol requirements. 6. Presence of other form of liver diseases (viral or autoimmune hepatitis, drug-induced liver disease, metabolic and hereditary liver disease and α-1 antitrypsin deficiency). 7. Subjects with accidental cases like injury, all types of anemias. 8. Subjects with Hemophilia, Thalassemia, case of poisoning, alcoholic liver, Alcoholic chronic liver disease, Decompensated cirrhosis 9. Chronic liver disease of different etiology (autoimmune disease, primary biliary cirrhosis, primary sclerosing cholangitis, hereditary hemochromatosis, Wilson's disease, deficits of alpha-1 antitrypsin, celiac disease). 10. Diseases, eczema, skin diseases/ allergy. 11. Malnutrition. 12. Severe renal, cardiac or respiratory insufficiency 13. Malignant tumors 14. Presence of secondary cause of NAFL such as medications that induce steatosis (corticosteroids, estrogens, methotrexate, amiodarone, tamoxifen and calcium channel blockers) and gastrointestinal bypass surgery. 15. Pharmacological treatment with some potential benefit on NAFL including ursodeoxycholic acid, vitamin E, betaine, pioglitazone, rosiglitazone, metformin, pentoxifylline or gemfibrozil. 16. Fasting glucose levels greater than 250 mg per deciliter (13.3 mmol per liter) 17. Contraindication to liver biopsy 18. Concomitant disease with reduced life expectancy. 19. Severe psychiatric conditions 20. Pregnant and breast feeding women. 2.3: Studied parameters All subjects were instructed to visit the site as per the scheduled visit. The IP accountability was cross checked at the time of visit and accounted in CRF. Follow up visits 2 (Day 28 ± 2 days), visit 3 (Day 56 ± 2 days) and visit 4 (day 84 ± 2 days) subjects were assessed for vital signs, physical examination, concomitant medication, adverse event/ serious adverse event reporting, subject diary assessment (for IP accountability) and dispensing of investigational product. Additionally on end of study visit (Visit 4: day 84 ± 2 days), subjects were assessed for retrieval of subject diary, retrieval of investigational product empty strips/container, measurement of liver stiffness by using USG, measurement of fatty liver index and HOMA-IR calculation, measurement of GSG index, QUICKI index and quality of life (SF 36) and laboratory investigations that included (haematology, bio-chemistry (albumin, fasting glucose, fasting insulin), liver function test (AST, ALT, GGT, bilirubin), lipid profile (Total Cholesterol, HDL, LDL, TG, Apo-B), kidney function test (urea and creatinine), stress and inflammatory biomarkers (CRP, IL-6, TNF-α), antioxidants (MDA, SOD, GSH), insulin sensitive parameter (QUICKI and HOMA IR Index), biomarker of NAFLD (GSG (Index)). Key results are summarized below. Group 1 Group 2 Group 3 (N=22) (N=22) (N=22) n (%) n (%) n (%) Average weight (Kg) 75.2 78.39 77.67 Dose of serine per day 0 64 129 (mg/Average weight in Kg) Number of Subjects Screened NA NA NA Number of screened failure NA NA NA subjects Number of Subjects Enrolled in the 22 22 22 (100) Study (100) (100) Number of Subjects who 22 (100) 20 (90.90) 21 (95.45) Completed the Study Number of Subjects Analysed for 22 22 22 (100) mITT Population (100) (100) Number of Subjects Analysed for 22 (100) 20 (90.90) 21 (95.45) PP Population Number of Subjects who 00 02 (9.09) 01 (4.55) Discontinued from the Study (00) Table 3: Summary of Subject Disposition– All subjects Example 3: Change in Fatty Liver Index The fatty liver index (FLI) is an algorithm based on waist circumference, body mass index (BMI), triglyceride, and gamma-glutamyl-transferase (GGT) for the prediction of fatty liver. The FLI was measured at baseline and at the end of the study using following formula. FLI = (e 0.953×loge (triglycerides) + 0.139×BMI + 0.718×loge (GGT) + 0.053×waist circumference − 15.745) / (1+e 0.953×loge (triglycerides) + 0.139×BMI + 0.718×loge (GGT) + 0.053×waist circumference − 15.745) × 100 Result: Group 1 Group 2 Group 3 Visit N=22 N=20 N=21 Baseline Mean 62.91 66.23 66.99 SD 21.48 20.81 25.07 End of Study M_ean 62.64 61.55 60.30 Group 1 Group 2 Group 3 Visit N=22 N=20 N=21 SD 21.93 23.02 28.40 Change from baseline Mean -0.27 -4.68 -6.70 SD -6.26 -8.07 -7.51 % change from baseline -0.28 8.33 14.17 P_-value G1 Vs G2 G1 Vs G3 0.049 0.002 Table 4: Fatty liver index (PP population) Conclusion: The results showed that, subjects in Group 3 has maximum % reduction in FLI which was found to be 14.17% at the end of the study visit. While subjects in other groups like Group 2 showed 8.33% and group 1 (controlled group) showed 0.28% improvement in FLI after 84 days of treatment. Example 4: Change in Liver Stiffness Liver stiffness was evaluated by Liver ultrasonography (USG) (like Edge, Periportal Echogenicity, Dome of Diaphragm, Parenchymal texture etc.) by Investigator/designee. Result: Group 1 Group 2 Group 3 Visit N=22 N=20 N=21 No. of subjects with change of Grade from Baseline No reduction 8 4 2 Reduction of 1 grade 14 16 19 Group 1 Group 2 Group 3 Visit N=22 N=20 N=21 % Subjects with change of Grade from Baseline N_{o reduction} ^{36.36 20.00 9.52} Reduction of 1 grade 63.64 80.00 90.48 Table 5: Change in Liver stiffness-Grade (PP population) Visit Group 1 Group 2 Group 3 Fisher exact test N=22 N=20 N=21 P values _Baseline _Irregular ^{22 20 21} >0.05 Regular 0 0 0 End of Study I^rregular _{8 4 0} _{14 16 2} >0.05 R^egular ₁ % Subject-EOS I_rregular 36.36 20.00 0.00 Regular 63.64 80.00 100.00 Table 6: Change in Liver stiffness- Edge (PP population) Visit Group 1 Group 2 Group 3 Fisher exact test N=22 N=20 N=21 P values Baseline Obscured 19 13 15 >0.05 Seen Clearly ^{3 7 6} End of Study Obscured 8 3 0 _{Seen Clearly} >0.05 1^{4 17 21} % Subject-EOS Obscured 36.36 15.00 0.00 - _{Seen Clearly} ^{63.64 85.00 100.00 -} Table 7: Change in Liver stiffness- Periportal Echogenicity (PP population) Conclusion: Group 3 showed major improvement in the liver stiffness evaluated by USG while comparing grade of liver stiffness, edge and periportal echogenicity. Only 2 subjects reported no reduction in grade of liver stiffness in group 3 after 84 days of treatment. The results showed that, subjects in Group 3 has 90.48% reduction in liver stiffness while subjects in other groups like Group1 and 2 showed 63.64% and 80.00% reduction in liver stiffness. While 100% of subjects improved in their edge and periportal echogenicity of USG. Example 5: Change in GSG Index (Glutamate serine glycine) Alterations of glutamate, glycine, and serine often occur in metabolic diseases. Particularly, glutamate concentrations were increased while glycine and serine were decreased in such type of diseases. The change in GSG Index was compared between the baseline visit (Day 1) and at the end of the study (Day 84 ±2 days). Result: Group 1 Group 2 Group 3 Visit ANOVA N=22 N=20 N=21 P values _Baseline Mean 0.28 0.31 0.36 >0.05 SD 0.17 0.19 0.13 End of Study Mean 0.3 0.25 0.26 >0.05 S_D 0.13 0.14 0.12 Change from ^baseline Mean 0.02 -0.06 -0.1 >0.05 SD 0.24 0.15 0.16 % 17.83 change from -46.96 8.61 (no baseline removal) P_-value G1 Vs G2 G1 Vs G3 - 0^.061 _0.027 - Table 8: Change in GSG Index (PP Population) Conclusion: The result showed that there was an improvement in % of change in GSG Index after Day 84 days of treatment. As per the result, % change in GSG index from baseline was recorded to be 17.83% and 8.61% after 84 days of treatment period in group 3 and group 2, respectively. There is worsening in the GSG index reported by subjects in Group 1 which was reported as -46.96%. Example 6: Change Triglyceride levels Triglyceride levels were measured at baseline and at the end of the study. Level of triglyceride has been evaluated at baseline and end of study visit. Result: Group 1 Group 2 Group 3 ANOVA Visit N=22 N=20 N=21 P values Baseline M_ean 125.45 162.10 148.10 >0.05 SD 48.27 83.66 69.40 End of Study Mean 148.27 146.20 112.10 >0.05 SD 70.16 76.96 38.93 Change from baseline Mean -22.82 15.90 36.00 >0.05 SD 59.15 40.91 57.14 P-value G1 Vs G2 G1 Vs G3 - 0.018 0.002 Table 9: Change in Tri Glyceride (PP Population) Conclusion: The results showed significant reduction in triglyceride in group 2 and group 3 compared to group 1 (controlled group). Example 7: Change in Malondialdehyde levels Malondialdehyde (MDA) is a byproduct of lipid peroxidation, a process where free radicals attack fatty acids in cell membranes. While it is a natural cellular process, excessive levels of MDA can be a sign of oxidative stress and damage to the liver. Reduction in Malondialdehyde levels and increase in levels of antioxidant Glutathione were evaluated at baseline and end of study visit. Result: Visit Group 1 Group 2 Group 3 ANOVA N=22 N=22 N=22 P values Baseline M_ean 2653.41 2877.27 3036.36 763.54 46 >0.05 SD 5.92 443.52 End of Study M_ean 1808.64 1437.00 1708.10 SD 947.28 718.87 945.77 >0.05 Change from baseline Mean -844.77 -1458.00 -1363.33 S_D 1078.78 723.90 954.90 >0.05 Table 10: Change in Malondialdehyde (MDA) ng/Ml (mITT Population) Conclusion: The results shows much higher reduction in Group 2 and Group 3 as compared to Group 1. Example 8: Change in Glutathione levels Glutathione (GSH) is a critical player in maintaining liver health, acting as the liver's master antioxidant and detoxifier. The level of glutathione were evaluated and compared between the baseline visit (Day 1) and at the end of the study (Day 84 ±2 days). Result: Visit Group 1 Group 2 Group 3 ANOVA N=22 N=22 N=22 P values Baseline Mean 4.84 3.00 3.93 S_D 3.93 0.84 3.49 >0.05 End of Study Mean 4.41 3.28 4.16 S_D >0.05 4.00 1.24 3.85 Change from baseline Mean -0.43 0.33 0.23 >0.05 SD 2.41 1.69 1.32 Table 11: Change in Glutathione (GSH) nmol/Ml (mITT Population) Conclusion: The results shows that in placebo Glutathione levels slightly declined while in Group 2 and Group 3 increase in glutathione levels is observed. Example 9: Improvement in Quality of Life The Quality of life was measured at baseline and at the end of the study by SF-36 questionnaire. Result: Visit Group 1 Group 2 Group 3 ANOVA N=22 N=22 N=22 P values Baseline Mean 47.50 40.00 38.18 S_D 14.78 12.82 11.08 >0.05 End of Study Mean 54.55 57.27 66.82 12.53 21.86 19. >0.05 SD 00 Change from baseline Mean 7.05 17.27 28.64 16. >0.05 SD 81 26.31 21.34 Table 12: Change in SF-36_Score_Physical functioning (mITT Population) Conclusion: It was clear from the results that, physical functioning is improved in group 3 with 38.18 (11.08) which is elevated to 66.82 (19.00) at the end of the study. In group 2 it was reported to increase to 57.27 (21.86) from 40.00 (12.82). No major change has been observed in group 1. Example 10: Other laboratory parameters testing The other laboratory parameters as mentioned below were measured at baseline and at the end of the study: 1. Liver Function Test (AST, ALT, GGT, Bilirubin) 2. Lipid profile Test (Total Cholesterol, HDL, LDL, TG, Apo-B) 3. Stress and inflammatory biomarkers (CRP, IL-6, TNF-α) Result: No significant difference was recorded HOMA-IR and BMI index. No statistically significant change was observed in any of the parameter in treatment groups. References – all incorporated herein by reference: 1. Lazarus JV, Colombo M, Cortez-Pinto H, Huang TTK, Miller V, Ninburg M, Schattenberg JM, Seim L, Wong VWS, Zelber-Sagi S. NAFLD – sounding the alarm on a silent epidemic. Nature Reviews Gastroenterology & Hepatology.2020 (17) 377-379. Green JG, Hodson L. The influence of dietary fat on liver fat accumulation. Nutrients.2014; 6(11):5018-5033. doi: 10.3390/nu6115018 Kaya E, Yilmaz Y. Metabolic-associated fatty liver disease (MAFLD): A multi-systemic disease beyond the liver. J. Clin. Transl. Hepatol. 2022; 10(2):329-338. Published online 2021 Oct 19. doi: 10.14218/JCTH.2021.00178 Riazi K, Azhari H, Charette JH, Underwood FE, King JA, Afshar EE. The prevalence and incidence of NAFLD worldwide: a systematic review and meta-analysis. The Lancet Gastroenterology & Hepatology. 2022;7(9):851-861. Published July 2, 2022 doi:

Huh Y, Cho YJ, Nam GE. Recent epidemiology and risk factors of nonalcoholic fatty liver disease. J Obes Metab Syndr.2022 Mar 30; 31(1): 17–27. Published online 2022 Mar 25. doi: 10.7570/jomes22021 Leivas G, Maraschin CK, Blume CA, Telo GH, Trindade MRM, Trindade EN, Diemen VV, Thadeu SC, Schaan BD. Accuracy of ultrasound diagnosis of nonalcoholic fatty liver disease in patients with classes II and III obesity: A pathological image study. Obesity Research and Clinical Practice 2021; 15(5):461-465. Stine JG, Munaganuru N, Barnard A, Wang JL, Kaulback K, Argo CK, Singh S, Fowler KJ, Sirlin CB, Loomba R. Change in MRI-PDFF and histologic response in patients with nonalcoholic stetohepatitis: a systematic review and meta-analysis. Clin Gastroenterol Hepatol 2021 Nov; 19(11):2274-2283.e5. Published online August 31, 2020. doi:

Bedogni G, Bellentani S, Miglioli L, Masutti F, Passalacqua M, Castiglione A, et al. The fatty liver index: A simple and accurate predictor of hepatic steatosis in the general population. BMC Gastroenterology. 2006;6(1). Ito Y, Takahashi S, Shen M, Yamaguchi K, Satoh M. Effects of L-serine ingestion on human sleep. Published online 2014 Aug 22. doi: 1801-3-456.

https://clinicaltrials.gov/ct2/show/NCT03580616. Sim WC, Yin HQ, Choi HS, et al. L-serine supplementation attenuates alcoholic fatty liver by enhancing homocysteine metabolism in mice and rats. J Nutr.2015;145(2):260-267. doi:10.3945/jn.114.199711 Reference needed to unpublished clinical trial / results on high dose L- serine for neurodegenerative diseases Mardinoglu A, Ural D, Zeybel M, Yuksel HH, Uhlén M, Borén J. The potential use of metabolic cofactors in treatment of NAFLD. Nutrients. 2019;11(7):1-17. doi:10.3390/nu11071578 Mardinoglu A, Bjornson E, Zhang C, et al. Personal model‐assisted identification of NAD + and glutathione metabolism as intervention target in NAFLD . Mol Syst Biol.2017;13(3):916. doi:10.15252/msb.20167422. Dandoy CE, Crouch BI , Caravati EM. Masking the smell and taste of acetylcysteine: what is the best option? Journal of Investigative Medicine Vol.54, Issue 1. 16. US2021095245A1 Mundhada H, Nielsen AT. Genetically modified microorganisms having improved tolerance towards L-Serine.

Claims

CLAIMS We claim, 1. A low dose formulation of L-serine for liver health and fatty liver diseases comprising daily dose of L-Serine is in the range of 25 mg/kg and 200 mg/kg body weight of a person and one or more excipients.

2. A low dose formulation of L-serine for liver health and fatty liver diseases as claimed in claim 1 further comprising bulking agent, diluent, acidity regulator and one or more excipients.

3. A low dose formulation of L-serine for liver health and fatty liver diseases as claimed in claim 2 wherein said bulking agent is selected from the group consisting of isomalt, lactitol, maltitol, mannitol, sorbitol, xylitol, lactose sucrose, dextran, and trehalose.

4. A low dose formulation of L-serine for liver health and fatty liver diseases as claimed in claim 2 wherein said bulking agent is used in the range of 0.83%w/w-16.66%w/w, preferably 1.66%w/w-16.66%w/w, more preferably 1.66%w/w-13.33%w/w, and most preferably 1.66%w/w- 8.33%w/w.

5. A low dose formulation of L-serine for liver health and fatty liver diseases as claimed in claim 2 wherein said diluent is selected from the group consisting of calcium carbonate, kaolin, sorbitol, maltodextrin, lactose, lactitol, maltose, and mannitol.

6. A low dose formulation of L-serine for liver health and fatty liver diseases as claimed in claim 2 wherein said diluent is used in the range of 0.83%w/w-16.66%w/w, preferably 1.66%w/w-16.66%w/w, more preferably 1.66%w/w-13.33%w/w, and most preferably 1.66%w/w- 8.33%w/w.

7. A low dose formulation of L-serine for liver health and fatty liver diseases as claimed in claim 2 wherein said acidity regulator is selected from the group consisting of fumaric acid, malic acid, citric acid, ascorbic acid, tartaric acid, lactic acid, and calcium acetate.

8. A low dose formulation of L-serine for liver health and fatty liver diseases as claimed in claim 2 wherein said acidity regulator is used in the range 0.016% w/w-1.66% w/w, preferably 0.16% w/w-1.66% w/w, more preferably 0.83% w/w-1.5 %w/w and most preferably 1-1.5% w/w.

9. The low dose formulation of L-serine for liver health and fatty liver diseases as claimed in claim 1, comprising the daily dose of L-Serine is between 25mg/kg and 200mg/kg body weight of a person, more preferably 50mg/kg and 160mg/kg of body weight of a person, more preferably 40mg/kg and 150mg/kg of body weight of a person, and most preferably 50 mg/kg and 130 mg/kg body weight of a person, and most preferably 64 mg/kg and 127 mg/kg body weight of a person.

10. The low dose formulation of L-serine for liver health and fatty liver diseases as claimed in claim 1 comprises one or more excipients being a flavour, sweetener, glidant, preservative or combinations thereof.

11. The low dose formulation of L-serine for liver health and fatty liver diseases as claimed in claim 1 in which the one or more excipient are one or more of the following: lemon flavor, orange flavor, xylitol, maltitol, sorbitol, polyglycitol, steviol glycoside, sodium propionate, sodium benzoate, benzoic acid, talc, magnesium stearate, stearic acid.

12. The low dose formulation of L-serine for liver health and fatty liver diseases as claimed in claim 1 in which the one or more excipient are one or more of the following: lemon flavor, steviol glycoside, magnesium stearate, and sodium benzoate.

13. The low dose formulation of L-serine for liver health and fatty liver diseases as claimed in claim 1 which is a dietary supplement.

14. The low dose formulation of L-serine for liver health and fatty liver diseases as claimed in claim 1 which is in the form of a powder.

15. The low dose formulation of L-serine for liver health and fatty liver diseases as claimed in claim 1 which is in the form of a liquid.

16. The low dose formulation of L-serine for liver health and fatty liver diseases as claimed in claim 1 which is in the form of a tablet.

17. The low dose formulation of L-serine for liver health and fatty liver diseases as claimed in claim 1 above which is for treatment of a fatty liver disease.

18. The low dose formulation of L-serine for liver health and fatty liver diseases as claimed in claim 1 which is for treatment of NAFLD.

19. The low dose formulation of L-serine for liver health and fatty liver diseases as claimed in claim 1 above which is for treatment of individuals at risk of developing a fatty liver disease.

20. A method of use of the low dose formulation of L-serine for liver health and fatty liver diseases as claimed in claim 1 where the use of the oral formulation is by once daily intake.

21. A method of use of the low dose formulation of L-serine for liver health and fatty liver diseases as claimed in claim 1 where the use of the oral formulation is by twice daily intake.

22. A method of use of the low dose formulation of L-serine for liver health and fatty liver diseases as claimed in claim 1 where the use of the oral formulation is by twice or more daily intake.