Caffeine stimulates hepatic lipid metabolism by the... : Hepatology (original) (raw)

Steatohepatitis and Metabolic Liver Disease

Caffeine stimulates hepatic lipid metabolism by the autophagy-lysosomal pathway in mice

Sinha, Rohit A.1; Farah, Benjamin L.1; Singh, Brijesh K.1; Siddique, Monowarul M.1; Li, Ying1; Wu, Yajun2; Ilkayeva, Olga R.3; Gooding, Jessica3; Ching, Jianhong1; Zhou, Jin1; Martinez, Laura1,4; Xie, Sherwin1; Bay, Boon-Huat2; Summers, Scott A.1,3; Newgard, Christopher B.3; Yen, Paul M.1,3

1_Program of Cardiovascular and Metabolic Disorders, Duke-NUS Graduate Medical School, Singapore_

2_Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, Singapore_

3_Sarah W. Stedman Nutrition and Metabolism Center, Departments of Medicine and Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC,_

4_Centro de Investigacion Biomedica en Red en el Area tematica de Enfermedades Hepaticas y Digestivas (CIBEREHD), Spain_

Received 5 June 2013; Accepted 30 July 2013

Address reprint requests to: Paul M. Yen, M.D., Duke-NUS Graduate Medical School, Laboratory of Hormonal Regulation, CVMD Program, 8 College Road, Singapore 018987. E-mail: [email protected]; fax: +65-6516-7396.

See Editorial on Page 1235

Potential conflict of interest: Nothing to report.

This work was supported by Duke-NUS Graduate Medical School Faculty Funds (to P.M.Y.) sponsored by the Ministry of Health, Ministry of Education, and Ministry of Trade, Singapore, and A*StaR and a National Institutes of Health grant (PO1DK58398; to C.B.N., L.M. acknowledges “Formacion de Personal Investigador” (FPI) and the reference BES-2009-027637 in the Spanish Ministry project with reference SAF2011-23031.

Additional Supporting Information may be found in the online version of this article.

Abstract

Caffeine is one of the world's most consumed drugs. Recently, several studies showed that its consumption is associated with lower risk for nonalcoholic fatty liver disease (NAFLD), an obesity-related condition that recently has become the major cause of liver disease worldwide. Although caffeine is known to stimulate hepatic fat oxidation, its mechanism of action on lipid metabolism is still not clear. Here, we show that caffeine surprisingly is a potent stimulator of hepatic autophagic flux. Using genetic, pharmacological, and metabolomic approaches, we demonstrate that caffeine reduces intrahepatic lipid content and stimulates β-oxidation in hepatic cells and liver by an autophagy-lysosomal pathway. Furthermore, caffeine-induced autophagy involved down-regulation of mammalian target of rapamycin signaling and alteration in hepatic amino acids and sphingolipid levels. In mice fed a high-fat diet, caffeine markedly reduces hepatosteatosis and concomitantly increases autophagy and lipid uptake in lysosomes. Conclusion: These results provide novel insight into caffeine's lipolytic actions through autophagy in mammalian liver and its potential beneficial effects in NAFLD. (HEPATOLOGY 2014;59:1366-1380)