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). Though 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 as a result of the coexistence of obesity and other cardiometabolic confounders. Adipose tissue is an emerging modulator of liver disease in NAFLD and of cardiometabolic disease in the general population. We evaluated in SS and NASH (1) glucose homeostasis and cardiovascular risk profile and (2) the effect 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 and 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, oxidized low-density lipoproteins, adipokines, and cytokeratin-18 fragments, and an oral glucose tolerance test with minimal model analysis to yield glucose homeostasis parameters. Circulating endothelial adhesion molecules were measured, and adipose tissue insulin resistance (adipose IR) index and visceral adiposity index were calculated. Despite similar fasting values, compared to SS, NASH showed a more atherogenic postprandial lipoprotein profile, an altered adipokine response (i.e., higher resistin increase and an adiponectin fall), and hepatocyte apoptosis activation after 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 cardiometabolic parameters. Adipose tissue dysfunction, including a maladaptive adipokine response to fat ingestion, modulates liver injury and cardiometabolic risk in NAFLD.

Musso G ，Cassader M ，De Michieli F ，Rosina F ，Orlandi F ，Gambino R ... -  《-》

Lipoprotein metabolism mediates the association of MTP polymorphism with beta-cell dysfunction in healthy subjects and in nondiabetic normolipidemic patients with nonalcoholic steatohepatitis.

Nonalcoholic steatohepatitis (NASH) predicts incident diabetes independently of insulin resistance, adiposity and metabolic syndrome through unclear mechanisms. Dietary fat consumption and lipoperoxidative stress predispose to diabetes in the general population and to liver injury in NASH. Microsomal triglyceride transfer protein (MTP) polymorphism modulates lipoprotein metabolism in the general population and liver disease in NASH; a functional MTP polymorphism recently predicted incident diabetes independently of insulin resistance in the general population. We simultaneously assessed the impact of MTP polymorphism, diet, adipokines and lipoprotein metabolism, on glucose homeostasis in NASH. MTP -493G/T polymorphism, dietary habits, adipokines and postprandial triglyceride-rich lipoproteins, high-density lipoprotein cholesterol (HDL-C) and oxidized low-density lipoprotein (oxLDL) responses to an oral fat load, were cross-sectionally correlated to oral glucose tolerance test- and frequently sampled intravenous glucose tolerance test-derived Minimal Model indexes of glucose homeostasis in 40 nondiabetic normolipidemic patients with NASH and 40 age-,sex- and body mass index-matched healthy controls. Despite comparable insulin resistance, fasting lipids, adipokines and dietary habits, MTP GG genotype had significantly more severe beta-cell dysfunction; higher plasma Tg, FFA, intestinal and hepatic very low-density lipoprotein 1 subfractions and oxLDL responses and deeper HDL-C fall than GT/TT carriers in patients and controls. Postprandial HDL-C and oxLDL responses independently predicted beta-cell dysfunction and mediated the effect of MTP polymorphism on beta-cell function. In nondiabetic normolipidemic NASH, MTP -493G/T polymorphism modulates beta-cell function, an effect mediated by postprandial HDL-C and oxLDL metabolism. The impact of this polymorphism on the risk of diabetes and the efficacy of lipid-lowering therapies in restoring beta-cell function in NASH, even with normal fasting lipid values, warrant further investigation.

Musso G ，Gambino R ，Cassader M 《-》

Adiponectin gene polymorphisms modulate acute adiponectin response to dietary fat: Possible pathogenetic role in NASH.

Musso G ，Gambino R ，De Michieli F ，Durazzo M ，Pagano G ，Cassader M ... -  《-》

Transcription factor 7-like 2 polymorphism modulates glucose and lipid homeostasis, adipokine profile, and hepatocyte apoptosis in NASH.

Musso G ，Gambino R ，Pacini G ，Pagano G ，Durazzo M ，Cassader M ... -  《-》

Polymorphism in microsomal triglyceride transfer protein: a link between liver disease and atherogenic postprandial lipid profile in NASH?

Gambino R ，Cassader M ，Pagano G ，Durazzo M ，Musso G ... -  《HEPATOLOGY》