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

Abstract

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 b-cell function. On multiple regression analysis, adipose IR index and postprandial adiponectin independently predicted liver histology and altered cardiometabolic parameters. Conclusion: Adipose tissue dysfunction, including a maladaptive adipokine response to fat ingestion, modulates liver injury and cardiometabolic risk in NAFLD. (HEPATOLOGY 2012;56:933-942)

Circulating phospholipid profiling identifies portal contribution to NASH signature in obesity

“…We confirmed the importance of fasting glycemia, HbA1c and adiponectinemia, linked to glucose homeostasis and NASH [33] [34]. Insulin resistance is common feature in NASH [35] [36]. Nevertheless, in the present study fasting insulin levels are equally elevated in NASH and no NASH subjects.…”

The effects of ezetimibe on non-alcoholic fatty liver disease and glucose metabolism: a randomised controlled trial

“…Insulin resistance was estimated by HOMA-IR, calculated as [fasting insulin (pmol/l) × fasting glucose (mmol/l)]/22.5 [12] and insulin sensitivity was estimated as the quantitative insulin sensitivity check index (QUICKI) [13]. The adipose tissue insulin resistance index (adipose IR) was calculated as fasting NEFA (mmol/l)×fasting insulin (pmol/l) [14][15][16]. The indocyanine green retention rate at 15 min after venous administration (ICG15) was assessed using standard laboratory techniques before and after treatment.…”

The therapeutic effects of bee venom on some metabolic and antioxidant parameters associated with HFD‑induced non‑alcoholic fatty liver in rats

“…During the pathogenesis of NAFLD, a crosstalk occurs between the liver and peripheral tissues such as the adipose tissue, skeletal muscle, and pancreas (2). Adipose tissue plays a pivotal role in the pathogenesis of NAFLD and the progression to steatohepatitis (3).…”