Salsalate and adiponectin ameliorate hepatic steatosis by inhibition of the hepatokine fetuin-A.
Fetuin-A was recently identified as a novel hepatokine which is associated with obesity, insulin resistance and non-alcoholic fatty liver disease. Salsalate, a prodrug of salicylate with an anti-inflammatory effect and lower side effect profile, significantly lowers glucose and triglyceride levels, and increased adiponectin concentrations in randomized clinical trials. In this study, we examined the effects and regulatory mechanisms of salsalate and full length-adiponectin (fAd) on fetuin-A expression, steatosis and lipid metabolism in palmitate-treated HepG2 cells. Incubation of hepatocytes with palmitate significantly increased fetuin-A and SREBP-1c expression which lead to steatosis and knock-down of fetuin-A by siRNA restored these changes. Salsalate significantly down-regulated palmitate-induced fetuin-A mRNA expression and secretion in a dose- and time-dependent manner. Inhibition of palmitate-induced fetuin-A by salsalate was mediated by AMPK-mediated reduction of NFκB activity, which was blocked by AMPK siRNA or an inhibitor of AMPK. Salsalate attenuated the excessive steatosis by palmitate through SREBP-1c regulation in hepatocytes. Furthermore, fAd also showed suppression of palmitate-induced fetuin-A through the AMPK pathway and improvement of steatosis accompanied by restoration of SREBP-1c, PAPR-α and CD36. In preliminary in vivo experiments, salsalate treatment inhibited high fat diet (HFD)-induced steatosis as well as fetuin-A mRNA and protein expression in SD rats. In conclusion, salsalate and fAd improved palmitate-induced steatosis and impairment of lipid metabolism in hepatocytes via fetuin-A inhibition through the AMPK-NFκB pathway.
Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Korea University, Seoul, Republic of Korea.
Tae Woo
TW
Jung
Byung-Soo
BS
Youn
Hae Yoon
HY
Choi
So Young
SY
Lee
Ho Cheol
HC
Hong
Sae Jeong
SJ
Yang
Hye Jin
HJ
Yoo
Baek-Hui
BH
Kim
Sei Hyun
SH
Baik
Kyung Mook
KM
Choi
D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D052242:Adiponectin / Q000494:pharmacology*; D000818:Animals; D059305:Diet, High-Fat / Q000009:adverse effects; D004195:Disease Models, Animal; D005234:Fatty Liver / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D056945:Hep G2 Cells / Q000187:drug effects; D006801:Humans; D050356:Lipid Metabolism / Q000187:drug effects; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D016328:NF-kappa B / Q000378:metabolism; D010168:Palmitates / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012459:Salicylates / Q000494:pharmacology*; D060749:alpha-2-HS-Glycoprotein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
D052242:Adiponectin; D016328:NF-kappa B; D010168:Palmitates; D012459:Salicylates; D060749:alpha-2-HS-Glycoprotein; D055372:AMP-Activated Protein Kinases; C014182:salicylsalicylic acid
AMPK; Adiponectin; ChIP; EMSA; Fetuin-A; HFD; Hepatokine; NAFLD; NF-κB; NFκB; Non-alcoholic fatty liver disease; Salicylate; Salsalate; adenosine monophosphate-activated protein kinase; chromatin immunoprecipitation assay; electrophoretic mobility-shift assay; fAd; full-length adiponectin; high fat diet; non-alcoholic fatty liver disease; nuclear factor-κB