Nutritional Genomics in Nonalcoholic Fatty Liver Disease

Abstract

Nonalcoholic fatty liver disease (NAFLD) is a common chronic condition associated with genetic and environmental factors in which fat abnormally accumulates in the liver. NAFLD is epidemiologically associated with obesity, type 2 diabetes, and dyslipidemia. Environmental factors, such as physical inactivity and an unbalanced diet, interact with genetic factors, such as epigenetic mechanisms and polymorphisms for the genesis and development of the condition. Different genetic polymorphisms seem to be involved in this context, including variants in PNPLA3, TM6SF2, PEMT, and CHDH genes, playing a role in the disease's susceptibility, development, and severity. From carbohydrate intake and weight loss to omega-3 supplementation and caloric restriction, different dietary and nutritional factors appear to be involved in controlling the onset and progression of NAFLD conditions influencing metabolism, gene, and protein expression. The polygenic risk score represents a sum of trait-associated alleles carried by an individual and seems to be associated with NAFLD outcomes depending on the dietary context. Understanding the exact extent to which lifestyle interventions and genetic predispositions can play a role in the prevention and management of NAFLD can be crucial for the establishment of a personalized and integrative approach to patients.

Keywords: CHDH; PEMT; PNPLA3; TM6SF2; diet; nonalcoholic fatty liver disease; nutrigenetics; nutrition; polygenic risk score.

Figure 1

Choline metabolism and PEMT pathway for de novo phosphatidylcholine synthesis [21]. BADH, betaine aldehyde dehydrogenase; CCT, phosphocholine cytidyltransferase; CDD, cytidine diphosphate-diacylglycerol; CDP-choline, cytidine diphosphocholine; CHDH, choline dehydrogenase; CHK, choline kinase; CPT, choline phosphotransferase; CTP, cytidine triphosphate; PEMT, phosphatidylethanolamine N-methyltransferase; SAH, S-adenosylhomocysteine; SAM, S-adenosylmethionine; SNP, single nucleotide polymorphisms; VLDL, very low-density lipoproteins. Interpretation: There are two pathways for phosphatidylcholine synthesis, CDP-choline pathway (green) and PEMT pathway (black). The first one is the main pathway and begins with free choline being phosphorylated by CHK to phosphocholine. Then, phosphocholine reacts with CTP forming CDP-choline with this reaction being catalyzed by CCT. Finally, to originate phosphatidylcholine, the enzyme CPT esterifies CDP-choline with diacylglycerol. The PEMT pathway begins with acyl-coenzyme A donating 2 acyl groups to 3-phosphoglycerate which is converted to phosphatidate. Phosphatidate and CTP can react and form CDD, whose hydroxyl group can react with serine forming phosphatidylserine that can be decarboxylated to phosphatidylethanolamine. In liver, phosphatidylethanolamine can be methylated to form phosphatidylcholine which has an important role in VLDL assembly and secretion. The methylation of phosphatidylethanolamine is catalyzed by PEMT, which need three molecules of SAM to form one molecule of phosphatidylcholine, and it releases three molecules of SAH. PEMT can have its activity enhanced in the presence of estrogens or impaired by SNP that make PEMT at some level estrogens-irresponsive. If phosphatidylcholine synthesis is compromised the triacylglycerols from VLDL accumulate in liver and may lead to the onset of NAFLD. Phosphatidylcholine can also form choline and starts its oxidation to betaine by a process composed by two enzymatic reactions (red). The first one produces betaine aldehyde by CHDH, and the second one forms betaine by BADH.

Figure 2

Nutritional genetics of NAFLD. Solid squares represent potential nutritional aspects and SNPs that positively affect NAFLD risk while non-solid squares represent nutritional aspects and SNPs that negatively affect NAFLD risk. Solid arrows indicate interaction while non-solid arrows indicate no interaction. PUFA-polyunsaturated fatty acids; PNPLA3-Patatin-like phospholipase domain-containing protein 3; CHDH-Choline Dehydrogenase; PEMT-Phosphatidylethanolamine NMethyltransferase; TM6SF2-Transmembrane 6 Superfamily Member 2; PRS-Polygenic Risk Score.