Effect of lectin-like oxidized LDL receptor-1 polymorphism on liver disease, glucose homeostasis, and postprandial lipoprotein metabolism in nonalcoholic steatohepatitis

Abstract

Nonalcoholic steatohepatitis (NASH) affects 3-5% of the general adult population and predisposes to cirrhosis, cardiovascular disease (CVD), and diabetes through unclear mechanisms. Lectin-like oxidized LDL receptor-1 (LOX-1) has been connected to CVD risk in the general population and to insulin resistance and hepatic fibrogenesis in experimental models. The objective was to assess the effect of the common functional LOX-1 IVS4-14 A→G polymorphism on liver disease, adipokines, oxidative stress, lipoprotein metabolism, and glucose homeostasis in NASH. Forty nonobese, nondiabetic, normolipidemic biopsy-proven NASH patients and 40 age-, sex-, BMI-, and LOX-1 IVS4-14 A→G polymorphism--matched healthy control subjects underwent an oral-fat-load test (OFT), with measurement of plasma triglyceride-rich lipoprotein (TRLP) subfractions, oxidized LDL, total antioxidant status (TAS), adipokines (resistin and adiponectin), and cytokeratin-18 fragments (marker of hepatocyte apoptosis). The subjects also underwent an oral-glucose-tolerance test (OGTT), with minimal model analysis to yield variables of glucose homeostasis. The LOX-1 polymorphism was independently associated with liver histology (G allele carriers had more severe liver disease); during the OFT, the G allele was associated with small TRLP accumulation, lower TAS, adipokine imbalance (higher resistin and lower adiponectin), and increased cytokeratin-18 fragments. The G allele was also independently associated with insulin resistance, impaired pancreatic β cell function, and incretin effect during the OGTT. In NASH, the LOX-1 polymorphism is associated with liver disease severity and may predispose to CVD through modulation of postprandial small TRLPs and adipokine balance and to diabetes by affecting both insulin secretion and insulin sensitivity.