PPAR-γ-induced changes in visceral fat and adiponectin levels are associated with improvement of steatohepatitis in patients with NASH.

Autor: Gastaldelli A; Diabetes Division, The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.; Institute of Clinical Physiology, National Research Council, CNR, Pisa, Italy., Sabatini S; Institute of Clinical Physiology, National Research Council, CNR, Pisa, Italy.; Università degli Studi di Siena, Siena, Italy., Carli F; Institute of Clinical Physiology, National Research Council, CNR, Pisa, Italy., Gaggini M; Institute of Clinical Physiology, National Research Council, CNR, Pisa, Italy., Bril F; Division of Endocrinology, Diabetes and Metabolism, University of Florida, Gainesville, FL, USA., Belfort-DeAguiar R; Department of Internal Medicine and Endocrinology, Yale University School of Medicine, New Haven, CT, USA., Positano V; Fondazione Toscana Gabriele Monasterio, Pisa, Italy., Barb D; Division of Endocrinology, Diabetes and Metabolism, University of Florida, Gainesville, FL, USA., Kadiyala S; Division of Endocrinology, Diabetes and Metabolism, University of Florida, Gainesville, FL, USA.; Division of Endocrinology, Diabetes and Metabolism, Malcom Randall Veteran Administration Medical Center at Gainesville, Gainesville, FL, USA., Harrison S; Pinnacle Clinical Research Group, San Antonio, TX, USA., Cusi K; Division of Endocrinology, Diabetes and Metabolism, University of Florida, Gainesville, FL, USA.; Division of Endocrinology, Diabetes and Metabolism, Malcom Randall Veteran Administration Medical Center at Gainesville, Gainesville, FL, USA.
Jazyk: angličtina
Zdroj: Liver international : official journal of the International Association for the Study of the Liver [Liver Int] 2021 Nov; Vol. 41 (11), pp. 2659-2670. Date of Electronic Publication: 2021 Jul 21.
DOI: 10.1111/liv.15005
Abstrakt: Background and Aims: Peroxisome proliferator-activated receptor (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 fat distribution (VF/SC) and adiponectin (ADPN) levels in relation to histological improvement after weight-loss or pioglitazone is relevant as novel PPAR-γ agonists are being developed for treating non-alcoholic steatohepatitis (NASH).
Methods: Fifty-five patients with NASH received a -500 kcal/d 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 35 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 (partial least square discriminant analysis [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 ADPN and a decrease in VF/SC, and to a lesser degree, improvement in oral glucose tolerance test-glucose concentrations and ALT. Decrease in steatosis and disease activity score (ballooning plus lobular inflammation) kept a close relationship with an increase in ADPN (r = -.71 and r = -.44, P < .007, respectively) and reduction in VF/SC fat (r = .41 and r = .37, P < .03 respectively).
Conclusions: Reduction in VF and improved VF/SC-distribution, combined with an increase in ADPN, 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.
(© 2021 The Authors. Liver International published by John Wiley & Sons Ltd.)
Databáze: MEDLINE
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