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

Journal article
Authors P Dongiovanni
S Stender
A Pietrelli
Rosellina Margherita Mancina
A Cespiati
S Petta
S Pelusi
Piero Pingitore
S Badiali
M Maggioni
V Mannisto
S Grimaudo
R M Pipitone
J Pihlajamaki
A Craxi
Magdalena Taube
Lena M S Carlsson
S Fargion
Stefano Romeo
J Kozlitina
L Valenti
Published in Journal of internal medicine
Volume 283
Issue 4
Pages 356-370
ISSN 1365-2796
Publication year 2018
Published at Institute of Medicine, Department of Molecular and Clinical Medicine
Pages 356-370
Language en
Keywords fibrosis, genetics, insulin resistance, mendelian randomization, nonalcoholic fatty liver disease, type 2 diabetes
Subject categories Clinical Medicine


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

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