Nonalcoholic steatohepatitis versus steatosis: Adipose tissue insulin resistance and dysfunctional response to fat ingestion predict liver injury and altered glucose and lipoprotein metabolism

Nonalcoholic fatty liver disease (NAFLD) ranges from simple steatosis (SS) to nonalcoholic steatohepatitis (NASH). While liver-related risk seems confined to NASH, it is currently unclear whether NASH has a higher risk of cardiovascular disease (CVD) and diabetes than SS, due to the coexistence of obesity and other cardio-metabolic confounders. Adipose tissue is an emerging modulator of liver disease in NAFLD and of cardio-metabolic disease in the general population. We evaluated in SS and NASH (1) glucose homeostasis and cardiovascular risk profile (2)the impact of adipose tissue dysfunction, assessed in fasting conditions and postprandially, on liver injury, glucose and lipoprotein metabolism, and markers of early atherosclerosis. Forty nonobese, nondiabetic, normolipidemic biopsy-proven NAFLD patients (20 with SS, 20 with NASH) and 40 healthy subjects, matched for overall/abdominal adiposity and metabolic syndrome, underwent: an oral fat load test with measurement of plasma triglyceride-rich lipoproteins, oxLDLs, adipokines, cytokeratin-18 fragments, and an OGTT with Minimal Model analysis to yield glucose homeostasis parameters. Circulating endothelial adhesion molecules were measured, and adipose tissue insulin resistance (adipose IR) index and the visceral adiposity index were calculated. Despite similar fasting values, compared to SS NASH showed a more atherogenic postprandial lipoprotein profile, an altered adipokine response (higher resistin increase and an adiponectin fall) and hepatocyte apoptosis activation following fat ingestion. Adipose IR index, endothelial adhesion molecules, and hepatic insulin resistance progressively increased across NAFLD stages. NASH, but not SS, showed an impaired pancreatic β-cell function. On multiple regression analysis, adipose IR index and postprandial adiponectin independently predicted liver histology and altered cardio-metabolic parameters. CONCLUSION.: Adipose tissue dysfunction, including an maladaptive adipokine response to fat ingestion, modulates liver injury and cardio-metabolic risk in NAFLD.