Steatohepatitis/Metabolic Liver Disease

Hepatic-specific activation of peroxisome proliferator-activated receptor γ coactivator-1β protects against steatohepatitis

Bellafante, Elena¹; Murzilli, Stefania¹; Salvatore, Lorena¹; Latorre, Dominga²; Villani, Gaetano²; Moschetta, Antonio^1,3,4,5,*

Author Information

¹Laboratory of Lipid Metabolism and Cancer, Department of Translational Pharmacology, Consorzio Mario Negri Sud, Santa Maria Imbaro (CH), Italy

²Department of Basic Medical Sciences, Neurosciences and Sense-organs, Biochemistry, Aldo Moro University of Bari, Italy

³Clinica Medica “A. Murri,” Interdisciplinar Department of Medicine, University of Bari, Italy

⁴National Cancer Institute Giovanni Paolo II, Bari, Italy

⁵National Institute for Digestive Diseases, IRCCS “S. de Bellis,” Castellana Grotte, Bari Italy

^*University of Bari, Consorzio Mario Negri Sud, Via Nazionale 8A, 66030 Santa Maria Imbaro (Chieti), Italy

Email:[email protected]

Received 20 June 2012; Accepted 16 October 2012

View this article online atwileyonlinelibrary.com.

Grant sponsor: Italian Association for Cancer Research (AIRC, Milan, Italy, IG 10416); Grant sponsor: Italian Ministry of Health and Education (Finanziamenti per la Ricerca di Base IDEAS RBID08C9N7); Grant sponsor: Italian Ministry of Health (Young Researchers Grant 2008, GR-2008-1143546); Grant sponsor: European Community's Seventh Framework Programme FP7/2007 — 2013 under Grant Agreement No. 202272 (LipidomicNet); Grant sponsor: Cariplo Fundation Milan, University of Bari, Italy (ORBA 08WEZJ, 07X7Q1, 06BXVC, IDEA GRBA0802SJ).

Potential conflict of interest: Nothing to report.

fax: +39-0872-570299

Hepatology 57(4):p 1343-1356, April 2013. | DOI: 10.1002/hep.26222

Abstract

Development of hepatic steatosis and its progression to steatohepatitis may be the consequence of dysfunction of several metabolic pathways, such as triglyceride synthesis, very low-density lipoprotein (VLDL) secretion, and fatty acid β-oxidation. Peroxisome proliferator-activated receptor γ coactivator-1β (PGC-1β) is a master regulator of mitochondrial biogenesis and oxidative metabolism, lipogenesis, and triglyceride (TG) secretion. Here we generated a novel mouse model with constitutive hepatic activation of PGC-1β and studied the role of this transcriptional coactivator in dietary-induced steatosis and steatohepatitis. Selective activation of PGC-1β within hepatocytes is able to protect the liver from lipid overload and from progression to fibrosis. The protective function exerted by PGC-1β is due to its ability to induce mitochondrial oxidative phosphorylation, fatty acid β-oxidation, and citrate cycle, as well as to decrease oxidative stress and promote TG secretion in the blood stream. These findings bolster the concept that a combined hepatic specific action of PGC-1β on lipid synthesis and secretion, as well as on mitochondrial biogenesis and function, could protect against steatohepatitis.