Causal relationship of hepatic fat with liver damage and insulin resistance in nonalcoholic fatty liver

J Intern Med. 2018 Apr;283(4):356-370. doi: 10.1111/joim.12719. Epub 2017 Dec 27.


Background and aims: Nonalcoholic fatty liver disease is epidemiologically associated with hepatic and metabolic disorders. The aim of this study was to examine whether hepatic fat accumulation has a causal role in determining liver damage and insulin resistance.

Methods: We performed a Mendelian randomization analysis using risk alleles in PNPLA3, TM6SF2, GCKR and MBOAT7, and a polygenic risk score for hepatic fat, as instruments. We evaluated complementary cohorts of at-risk individuals and individuals from the general population: 1515 from the liver biopsy cohort (LBC), 3329 from the Swedish Obese Subjects Study (SOS) and 4570 from the population-based Dallas Heart Study (DHS).

Results: Hepatic fat was epidemiologically associated with liver damage, insulin resistance, dyslipidemia and hypertension. The impact of genetic variants on liver damage was proportional to their effect on hepatic fat accumulation. Genetically determined hepatic fat was associated with aminotransferases, and with inflammation, ballooning and fibrosis in the LBC. Furthermore, in the LBC, the causal association between hepatic fat and fibrosis was independent of disease activity, suggesting that a causal effect of long-term liver fat accumulation on liver disease is independent of inflammation. Genetically determined hepatic steatosis was associated with insulin resistance in the LBC and SOS. However, this association was dependent on liver damage severity. Genetically determined hepatic steatosis was associated with liver fibrosis/cirrhosis and with a small increase in risk of type 2 diabetes in publicly available databases.

Conclusion: These data suggest that long-term hepatic fat accumulation plays a causal role in the development of chronic liver disease.

Keywords: fibrosis; genetics; insulin resistance; mendelian randomization; nonalcoholic fatty liver disease; type 2 diabetes.

Publication types

  • Multicenter Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acyltransferases / genetics
  • Adaptor Proteins, Signal Transducing / genetics
  • Adipose Tissue / physiology*
  • Adult
  • Chronic Disease
  • Diabetes Mellitus, Type 2 / complications
  • Female
  • Genetic Markers / genetics
  • Humans
  • Insulin Resistance / physiology*
  • Lipase / genetics
  • Liver Cirrhosis / etiology*
  • Male
  • Membrane Proteins / genetics
  • Mendelian Randomization Analysis
  • Non-alcoholic Fatty Liver Disease / complications*
  • Prospective Studies


  • Adaptor Proteins, Signal Transducing
  • GCKR protein, human
  • Genetic Markers
  • Membrane Proteins
  • TM6SF2 protein, human
  • Acyltransferases
  • MBOAT7 protein, human
  • Lipase
  • adiponutrin, human