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Abstract Details
PPAR-?-induced Changes in Visceral Fat and Adiponectin Levels are Associated with Improvement of Steatohepatitis in Patients with NASH
7Division of Endocrinology, Diabetes and Metabolism, Malcom Randall Veteran Administration Medical Center at Gainesville, Florida, USA.
8Pinnacle Clinical Research Group, San Antonio, Texas, USA.
Abstract
Background&aims: PPAR-γ agonists decrease hepatic/visceral fat (VF) and improve necroinflammation despite subcutaneous (SC) fat weight-gain. Understanding the impact of changes in VF, VF-to-SC distribution (VF/SC) and adiponectin levels in relation to histological improvement after weight-loss or pioglitazone is relevant as novel PPAR-γ agonists are being developed for treating NASH.
Methods: Fifty-five patients with NASH received a -500 kcal/day hypocaloric diet and were randomized (double-blind) to pioglitazone (45 mg/d) or placebo for 6-months. Before and after treatment patients underwent a liver biopsy and measurement of hepatic/peripheral glucose fluxes, hepatic/adipose tissue-IR and, in thirty-five patients, hepatic and VF/SC-fat was measured by magnetic resonance spectroscopy/imaging. Data were examined by multivariable statistical analyses combined with machine-learning techniques (PLS-DA).
Results: Both pioglitazone (despite weight-gain) and placebo (if weight-loss) reduced steatosis but only pioglitazone ameliorated necroinflammation. Using machine-learning PLS-DA showed that the treatment differences induced by a PPAR-γ agonist vs. placebo on metabolic variables and liver histology could be best explained by the increase in adiponectin and a decrease in VF/SC, and to a lesser degree, improvement in OGTT-glucose concentrations and ALT. Decrease in steatosis and disease activity score (ballooning plus lobular inflammation) kept a close relationship with an increase in adiponectin (r=-0.71 and r=-0.44, p< 0.007, respectively) and reduction in VF/SC (r=0.41 and r=0.37, p<0.03, respectively).
Conclusions: Reduction in VF and improved VF/SC-distribution, combined with an increase in adiponectin, mediate the histological benefits of PPAR-γ action, highlighting the central role of fat metabolism and its distribution on steatohepatitis disease activity in patients with NASH.