Dimethyl α-ketoglutarate reduces CCl4-induced liver fibrosis through inhibition of autophagy in hepatic stellate cells.
Sustained activation of hepatic stellate cells (HSCs) leads to liver fibrosis. Autophagy fuels the activation of HSCs by generation of ATP. Our previous research demonstrated an inhibitory effect of dimethyl α-ketoglutarate (DMKG) on HSCs activation in vitro. In the current study, we demonstrated that DMKG reduced CCl4-induced liver fibrosis in Wistar rats. Then, with the use of the HSC-T6 cell lines and double immunofluorescent staining of liver sections, we showed that the anti-fibrotic effect occurred through the inhibition of the autophagy of HSCs. Both experiments showed that DMKG could inhibit autophagy and activation of HSCs, and that the activation of HSCs was down-regulated with autophagy. In addition, we showed that DMKG could lead to lipid droplet accumulation and decrease cellular ATP content in HSCs. Furthermore, the mechanism of how DMKG inhibited autophagy of HSCs was explored in vitro with the use of c646 (a competitive inhibitor of acetyl-coenzyme A which binds to the acetyltransferase EP300) and lipoic acid (an alternative acetyl-coenzyme A -replenishing agent to DMKG), and showed that both acetyl-coenzyme A and EP300 were involved. Collectively, our study investigated the possible role of DMKG in preventing liver fibrosis and HSCs activation. We showed that DMKG may be a potential therapeutic agent for the treatment of liver fibrosis.
Department of Geriatric Gastroenterology, Qilu Hospital of Shandong University, Jinan, 250012, China. Electronic address: doctorxiaozhao@163.com.
Jianjian
J
Zhao
Department of Geriatric Gastroenterology, Qilu Hospital of Shandong University, Jinan, 250012, China.
Lei
L
Peng
Department of Geriatric Gastroenterology, Qilu Hospital of Shandong University, Jinan, 250012, China.
Ruibing
R
Cui
Department of Geriatric Gastroenterology, Qilu Hospital of Shandong University, Jinan, 250012, China.
Xiaolan
X
Guo
Department of Geriatric Gastroenterology, Qilu Hospital of Shandong University, Jinan, 250012, China. Electronic address: ymylh@163.com.
Ming
M
Yan
D000818:Animals; D001343:Autophagy / Q000187:drug effects*; D002251:Carbon Tetrachloride; D004305:Dose-Response Relationship, Drug; D055166:Hepatic Stellate Cells / Q000187:drug effects* / Q000473:pathology*; D007656:Ketoglutaric Acids / Q000494:pharmacology*; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000473:pathology* / Q000517:prevention & control*; D051381:Rats; D017208:Rats, Wistar; D016896:Treatment Outcome
D007656:Ketoglutaric Acids; C541783:dimethyl alpha-ketoglutarate; D002251:Carbon Tetrachloride
Autophagy; Dimethyl α-ketoglutarate; EP300; Hepatic stellate cell; Liver fibrosis