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

• Published in: Journal of internal medicine Vol. 283; no. 4; pp. 356 - 370
• Main Authors: Dongiovanni, P., Stender, S., Pietrelli, A., Mancina, R. M., Cespiati, A., Petta, S., Pelusi, S., Pingitore, P., Badiali, S., Maggioni, M., Mannisto, V., Grimaudo, S., Pipitone, R. M., Pihlajamaki, J., Craxi, A., Taube, M., Carlsson, L. M.S., Fargion, S., Romeo, S., Kozlitina, J., Valenti, L.
• Format: Journal Article
• Language: English
• Published: England Blackwell Publishing Ltd 01.04.2018; John Wiley and Sons Inc
• Subjects: Accumulation; Acyltransferases - genetics; Adaptor Proteins, Signal Transducing - genetics; Adipose Tissue - physiology; Adult; Biopsy; Chronic Disease; Cirrhosis; Clinical Medicine; Damage accumulation; Diabetes mellitus; Diabetes mellitus (non-insulin dependent); Diabetes Mellitus, Type 2 - complications; Dyslipidemia; Epidemiology; Fatty liver; Female; Fibrosis; Genetic diversity; Genetic Markers - genetics; Genetic variance; genetics; Health risks; Humans; Hypertension; Impact damage; Insulin; Insulin resistance; Insulin Resistance - physiology; Klinisk medicin; Lipase - genetics; Liver; Liver cirrhosis; Liver Cirrhosis - etiology; Liver diseases; Male; Membrane Proteins - genetics; mendelian randomization; Mendelian Randomization Analysis; Metabolic disorders; Non-alcoholic Fatty Liver Disease - complications; nonalcoholic fatty liver disease; Original; Population studies; Prospective Studies; Risk analysis; Steatosis; type 2 diabetes; nonalcoholic fatty liver disease; fibrosis; genetics; type 2 diabetes; insulin resistance; mendelian randomization
• ISSN: 0954-6820; 1365-2796; 1365-2796
• DOI: 10.1111/joim.12719

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.