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

Abstract

Background and AimsNonalcoholic 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.MethodsWe 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).ResultsHepatic 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.ConclusionThese data suggest that long‐term hepatic fat accumulation plays a causal role in the development of chronic liver disease.

Protein phosphatase 1 regulatory subunit 3B gene variation protects against hepatic fat accumulation and fibrosis in individuals at high risk of nonalcoholic fatty liver disease

“…Despite previous contrasting evidence,8, 9, 10, 11, 12, 13 these novel data lend strong support to the hypothesis that the PPP1R3B variation does protect against hepatic fat accumulation, at least in at‐risk individuals. Furthermore, they support the notion that steatosis is a major driver of liver disease progression to fibrosis7 and HCC18 in individuals with NAFLD.…”

“…NAFLD has a strong genetic component, and variants in proteins regulating hepatocellular lipid handling, including patatin‐like phospholipase domain‐containing 3 ( PNPLA3 ), transmembrane 6 superfamily member 2 ( TM6SF2 ), membrane bound O‐acyltransferase domain‐containing 7 ( MBOAT7 ), and glucokinase regulator ( GCKR ), predispose to the development and progression to nonalcoholic steatohepatitis (NASH), which is the inflammatory form of NAFLD, and to hepatic fibrosis,4, 5 which is the major prognostic determinant in patients with NAFLD 6. By exploiting naturally occurring variation at these loci, we recently highlighted by a Mendelian randomization approach that hepatic fat accumulation is a key driver of liver disease progression and fibrosis development in at‐risk individuals 7. However, whether this is generalizable to other risk factors for NAFLD development and progression and for protective variants remains to be demonstrated.…”

Saturated Fat Is More Metabolically Harmful for the Human Liver Than Unsaturated Fat or Simple Sugars

“…NAFLD has been shown to predict type 2 diabetes and cardiovascular disease in multiple studies, even independent of obesity (1), and also to increase the risk of progressive liver disease (17). It is therefore interesting to compare effects of different diets on liver fat content and understand the underlying mechanisms.…”

“…These percentages were twofold higher than in the CARB group (24% [20][21][22][23][24][25][26]) (Supplementary Table 1). Saturated fat intake was twofold higher in the SAT group (33% [28][29][30][31][32][33][34][35][36]) than in the UNSAT group (14% [14][15][16][17][18], P , 0.001). Monounsaturated (28% [23][24][25][26][27][28][29][30] UNSAT vs. 13% [12][13][14][15] SAT, P , 0.001) and polyunsaturated (11% [10][11][12][13][14] UNSAT vs. 5% [4][5] SAT, P , 0.001) fat intakes were twofold higher in the UNSAT than in the SAT group.…”

Apolipoprotein B and PNPLA3 Double Heterozygosity in a Father–Son Pair With Advanced Nonalcoholic Fatty Liver Disease

“…This lipoprotein assembly machinery and transport are, however, crippled in homozygotes. Fat retention in the liver may play a causal role in chronic liver disease according to a recent Mendelian randomization study . Furthermore, individuals with HCC related to NAFLD have an enrichment in inherited pathogenic variants, in particular APOB …”