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


CONCLUSIONS
These results provide novel insight into caffeine's lipolytic actions through autophagy in mammalian liver and its potential beneficial effects in NAFLD.
Program of Cardiovascular and Metabolic Disorders, Duke-NUS Graduate Medical School, Singapore.
Rohit A
RA
Sinha
Benjamin L
BL
Farah
Brijesh K
BK
Singh
Monowarul M
MM
Siddique
Ying
Y
Li
Yajun
Y
Wu
Olga R
OR
Ilkayeva
Jessica
J
Gooding
Jianhong
J
Ching
Jin
J
Zhou
Laura
L
Martinez
Sherwin
S
Xie
Boon-Huat
BH
Bay
Scott A
SA
Summers
Christopher B
CB
Newgard
Paul M
PM
Yen
D000818:Animals; D001343:Autophagy / Q000187:drug effects* / Q000502:physiology; D002110:Caffeine / Q000494:pharmacology* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D059305:Diet, High-Fat / Q000009:adverse effects; D015536:Down-Regulation / Q000187:drug effects; D005234:Fatty Liver / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control; D056945:Hep G2 Cells; D006801:Humans; D066298:In Vitro Techniques; D050356:Lipid Metabolism / Q000187:drug effects*; D008066:Lipolysis / Q000187:drug effects / Q000502:physiology; D008099:Liver / Q000187:drug effects* / Q000378:metabolism*; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology; D008247:Lysosomes / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D010084:Oxidation-Reduction / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
D002110:Caffeine; D058570:TOR Serine-Threonine Kinases