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Nonalcoholic fatty liver disease (NAFLD) is the most common form of liver disease. To elucidate the molecular basis of NAFLD, we performed an exome-wide association study of liver fat content. Three variants were associated with higher liver fat levels at the exome-wide significance level of 3.6 × 10−7: two in PNPLA3, an established locus for NAFLD, and one (encoding p.Glu167Lys) in TM6SF2, a gene of unknown function. The TM6SF2 variant encoding p.Glu167Lys was also associated with higher circulating levels of alanine transaminase, a marker of liver injury, and with lower levels of low-density lipoprotein-cholesterol (LDL-C), triglycerides and alkaline phosphatase in 3 independent populations (n > 80,000). When recombinant protein was expressed in cultured hepatocytes, 50% less Glu167Lys TM6SF2 protein was produced relative to wild-type TM6SF2. Adeno-associated virus-mediated short hairpin RNA knockdown of Tm6sf2 in mice increased liver triglyceride content by threefold and decreased very-low-density lipoprotein (VLDL) secretion by 50%. Taken together, these data indicate that TM6SF2 activity is required for normal VLDL secretion and that impaired TM6SF2 function causally contributes to NAFLD. [ABSTRACT FROM AUTHOR]

OBJECTIVES:We tested the hypothesis that alcohol, alone and in combination with alcohol dehydrogenase (ADH) 1B and ADH1C genotypes, affects liver damage and disease in the general population.METHODS:Information on alcohol intake and on liver disease was obtained from 9,080 men and women from the Copenhagen City Heart Study. Biochemical tests for the detection of liver damage were specific for alanine aminotransferase (ALT), aspartate aminotransferase (AST)-to-ALT ratio (AST/ALT), γ-glutamyl transpeptidase (γ-GT), albumin, bilirubin, alkaline phosphatase, coagulation factors, and erythrocyte volume.RESULTS:Increasing alcohol intake was associated with increasing erythrocyte volume, AST/ALT, and levels of ALT, γ-GT, albumin, bilirubin, coagulation factors, and with decreasing levels of alkaline phosphatase. Multifactorially adjusted hazard ratios for alcoholic liver disease overall were 0.9 (95% confidence interval (CI), 0.6–1.4), 1.4 (0.8–2.5), 1.8 (0.9–3.5), and 4.1 (2.5–7.0) for an alcohol intake of 1–13, 14–20, 21–27, and ≥28 drinks per week, respectively, compared with drinking <1 drink per week (P for trend<0.0001); the corresponding hazard ratios for alcoholic liver cirrhosis were 1.7 (0.6–4.7), 2.0 (0.8–7.1), 6.5 (2.0–21), and 13 (4.6–37) (P for trend<0.0001). ADH1B and ADH1C genotypes were not associated with and did not modify the effect of alcohol on biochemical tests or risk of liver disease.CONCLUSIONS:Increasing alcohol intake from none to low (1–6 drinks per week) through to moderate (7–20 drinks per week) and excessive intake (≥21 drinks per week) leads to stepwise increases in signs of liver damage with no threshold effect, and to an increased risk of liver disease. The minor changes in biochemical tests for low alcohol intake may not account for subclinical liver disease. [ABSTRACT FROM AUTHOR]