Resveratrol improves hepatic steatosis by inducing autophagy through the cAMP signaling pathway.
METHODS
Resveratrol (RSV), a natural polyphenol, has been reported to attenuate nonalcoholic fatty liver disease (NAFLD); however, its underlying mechanism is unclear. Autophagy was recently identified as a critical protective mechanism during NAFLD development. Therefore, we investigated the role of autophagy in the beneficial effects of RSV on hepatic steatosis.


RESULTS
Via Oil red O staining, triglyceride, and β-hydroxybutyrate detection, we found that RSV decreased palmitate-induced lipid accumulation and stimulated fatty acid β-oxidation in hepatocytes. Based on Western blot assay, confocal microscopy and transmission electron microscopy, we found that RSV induced autophagy in hepatocytes, whereas autophagy inhibition markedly abolished RSV-mediated hepatic steatosis improvement. Moreover, RSV increased cAMP levels and the levels of SIRT1 (sirtuin 1), pPRKA (phosphorylated protein kinase A), and pAMPK (phosphorylated AMP-activated protein kinase), as well as SIRT1 activity in HepG2 cells. Incubation with inhibitors of AC (adenylyl cyclase), PRKA, AMPK, SIRT1, or with AC, PRKA, AMPK, or SIRT1 siRNA abolished RSV-mediated autophagy. Similar results were obtained in mice with hepatic steatosis.


CONCLUSIONS
RSV improved hepatic steatosis partially by inducing autophagy via the cAMP-PRKA-AMPK-SIRT1 signaling pathway, which provides new evidence regarding RSV's effects on NAFLD treatment.
Research Center for Nutrition and Food Safety, Institute of Military Preventive Medicine, Third Military Medical University, Chongqing, P. R. China.
Yong
Y
Zhang
Research Center for Nutrition and Food Safety, Institute of Military Preventive Medicine, Third Military Medical University, Chongqing, P. R. China.
Ming-liang
ML
Chen
Research Center for Nutrition and Food Safety, Institute of Military Preventive Medicine, Third Military Medical University, Chongqing, P. R. China.
Yong
Y
Zhou
Research Center for Nutrition and Food Safety, Institute of Military Preventive Medicine, Third Military Medical University, Chongqing, P. R. China.
Long
L
Yi
Research Center for Nutrition and Food Safety, Institute of Military Preventive Medicine, Third Military Medical University, Chongqing, P. R. China.
Yan-xiang
YX
Gao
Research Center for Nutrition and Food Safety, Institute of Military Preventive Medicine, Third Military Medical University, Chongqing, P. R. China.
Li
L
Ran
Research Center for Nutrition and Food Safety, Institute of Military Preventive Medicine, Third Military Medical University, Chongqing, P. R. China.
Shi-hui
SH
Chen
Research Center for Nutrition and Food Safety, Institute of Military Preventive Medicine, Third Military Medical University, Chongqing, P. R. China.
Ting
T
Zhang
Research Center for Nutrition and Food Safety, Institute of Military Preventive Medicine, Third Military Medical University, Chongqing, P. R. China.
Xi
X
Zhou
Research Center for Nutrition and Food Safety, Institute of Military Preventive Medicine, Third Military Medical University, Chongqing, P. R. China.
Dan
D
Zou
Research Center for Nutrition and Food Safety, Institute of Military Preventive Medicine, Third Military Medical University, Chongqing, P. R. China.
Bin
B
Wu
Research Center for Nutrition and Food Safety, Institute of Military Preventive Medicine, Third Military Medical University, Chongqing, P. R. China.
Ying
Y
Wu
Research Center for Nutrition and Food Safety, Institute of Military Preventive Medicine, Third Military Medical University, Chongqing, P. R. China.
Hui
H
Chang
Research Center for Nutrition and Food Safety, Institute of Military Preventive Medicine, Third Military Medical University, Chongqing, P. R. China.
Jun-dong
JD
Zhu
Research Center for Nutrition and Food Safety, Institute of Military Preventive Medicine, Third Military Medical University, Chongqing, P. R. China.
Qian-yong
QY
Zhang
Research Center for Nutrition and Food Safety, Institute of Military Preventive Medicine, Third Military Medical University, Chongqing, P. R. China.
Man-tian
MT
Mi
D000262:Adenylyl Cyclases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000378:metabolism / Q000627:therapeutic use*; D001343:Autophagy / Q000187:drug effects; D000242:Cyclic AMP / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000378:metabolism; D019587:Dietary Supplements; D004790:Enzyme Induction / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005230:Fatty Acids, Nonesterified / Q000009:adverse effects / Q000037:antagonists & inhibitors / Q000378:metabolism; D056945:Hep G2 Cells; D006801:Humans; D050356:Lipid Metabolism / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D057507:Mice, 129 Strain; D046529:Microscopy, Electron, Transmission; D065626:Non-alcoholic Fatty Liver Disease / Q000178:diet therapy* / Q000378:metabolism / Q000473:pathology; D034622:RNA Interference; D000077185:Resveratrol; D015290:Second Messenger Systems / Q000187:drug effects; D056564:Sirtuin 1 / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D013267:Stilbenes / Q000378:metabolism / Q000627:therapeutic use*
D000975:Antioxidants; D004791:Enzyme Inhibitors; D005230:Fatty Acids, Nonesterified; D013267:Stilbenes; D000242:Cyclic AMP; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1; D000262:Adenylyl Cyclases; D000077185:Resveratrol
Hepatocyte; NAFLD; Resveratrol; SIRT1; Treatment