Insights from Genome-Wide Association Analyses of Nonalcoholic Fatty Liver Disease

Abstract

Nonalcoholic fatty liver disease (NAFLD) is caused by hepatic steatosis, which can progress to nonalcoholic steatohepatitis, fibrosis/cirrhosis, and hepatocellular carcinoma in the absence of excessive alcohol consumption. Nonalcoholic fatty liver disease will become the number one cause of liver disease worldwide by 2020. Nonalcoholic fatty liver disease is correlated albeit imperfectly with obesity and other metabolic diseases such as diabetes, hyperlipidemia, and cardiovascular disease, but exactly how having one of these diseases contributes to the development of other metabolic diseases is only now being elucidated. Development of NAFLD and related metabolic diseases is genetically influenced in the population, and recent genome-wide association studies (GWASs) have discovered genetic variants that associate with these diseases. These GWAS-associated variants cannot only help us to identify individuals at high risk of developing NAFLD, but also to better understand its pathophysiology so that we can develop more effective treatments for this disease and related metabolic diseases in the future.

Fig. 1

Cellular localization of some genes/gene products associated with nonalcoholic fatty liver disease (NAFLD) from genome-wide association studies (GWASs). Genes implicated by GWASs in blue. Glucokinase regulator protein (GCKR) binds to and inactivates glucokinase (GK) by bringing it into the nucleus, thus decreasing phosphorylation of glucose to glucose 6-phosphate, which is a precursor for both glycogen and triglyceride synthesis. Loss of GCKR thus might promote triglyceride synthesis and hepatic steatosis. Protein phosphatase 1 (PPP1R3B) promotes glycogen synthesis and inhibits glycogen breakdown to phosphorylated glucose which can be used to make triglycerides and promote hepatic steatosis; patatin-like phospholipase domain-containing protein 3 (PNPLA3) is present on lipid droplets, but its exact biochemical function is debated; the NAFLD promoting I148M mutation, however, results in increased triglyceride storage in lipid droplets and hepatic steatosis. Transmembrane protein 6 (TM6SF2) is in the perinuclear endoplasmic reticulum- interference with its function results in impaired very low-density lipoprotein cholesterol (VLDL) excretion, accumulation of triglycerides in the cell, and hepatic steatosis. Tribbles 1 homolog (TRIB1) inhibits de novo lipogenesis so its loss thus promotes fatty acid production, triglyceride (TG) synthesis, and hepatic steatosis. G6P, glucose 6-phosphate.

Fig. 2

Factors that interact with PNPLA3 I148M to exacerbate liver disease development. PUFA, polyunsaturated fatty acid.