title: Hydrogen sulfide reduces serum triglyceride by activating liver autophagy via the AMPK-mTOR pathway.
abstract: Autophagy plays an important role in liver triglyceride (TG) metabolism. Inhibition of autophagy could reduce the clearance of TG in the liver. Hydrogen sulfide (H2S) is a potent stimulator of autophagic flux. Recent studies showed H2S is protective against hypertriglyceridemia (HTG) and noalcoholic fatty liver disease (NAFLD), while the mechanism remains to be explored. Here, we tested the hypothesis that H2S reduces serum TG level and ameliorates NAFLD by stimulating liver autophagic flux by the AMPK-mTOR pathway. The level of serum H2S in patients with HTG was lower than that of control subjects. Sodium hydrosulfide (NaHS, H2S donor) markedly reduced serum TG levels of male C57BL/6 mice fed a high-fat diet (HFD), which was abolished by coadministration of chloroquine (CQ), an inhibitor of autophagic flux. In HFD mice, administration of NaSH increased the LC3BII-to-LC3BI ratio and decreased the p62 protein level. Meanwhile, NaSH increased the phosphorylation of AMPK and thus reduced the phosphorylation of mTOR in a Western blot study. In cultured LO2 cells, high-fat treatment reduced the ratio of LC3BII to LC3BI and the phosphorylation of AMPK, which were reversed by the coadministration of NaSH. Knockdown of AMPK by siRNA in LO2 cells blocked the autophagic enhancing effects of NaSH. The same qualitative effect was observed in AMPKα2(-/-) mice. These results for the first time demonstrated that H2S could reduce serum TG level and ameliorate NAFLD by activating liver autophagy via the AMPK-mTOR pathway.
authors.affiliation: Department of Cardiology, the First Affiliated Hospital, Harbin Medical University, Harbin, Heilongjiang Province, China;
authors.forename: Li
authors.initials: L
authors.lastname: Sun
authors.affiliation: Department of Cardiology, the First Affiliated Hospital, Harbin Medical University, Harbin, Heilongjiang Province, China;
authors.forename: Song
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Department of Cardiology, the First Affiliated Hospital, Harbin Medical University, Harbin, Heilongjiang Province, China;
authors.forename: Chengyuan
authors.initials: C
authors.lastname: Yu
authors.affiliation: Department of Pharmacology, Harbin Medical University, Harbin, Heilongjiang Province, China.
authors.forename: Zhenwei
authors.initials: Z
authors.lastname: Pan
authors.affiliation: Department of Cardiology, the First Affiliated Hospital, Harbin Medical University, Harbin, Heilongjiang Province, China;
authors.forename: Yang
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Key Laboratory of Cardiac Diseases and Heart Failure, Harbin Medical University, Harbin, Heilongjiang Province, China; and.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Department of Cardiology, the First Affiliated Hospital, Harbin Medical University, Harbin, Heilongjiang Province, China;
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Cardiology, the First Affiliated Hospital, Harbin Medical University, Harbin, Heilongjiang Province, China;
authors.forename: Fengxiang
authors.initials: F
authors.lastname: Yun
authors.affiliation: Department of Cardiology, the First Affiliated Hospital, Harbin Medical University, Harbin, Heilongjiang Province, China;
authors.forename: Hongwei
authors.initials: H
authors.lastname: Zhao
authors.affiliation: Department of Cardiology, the First Affiliated Hospital, Harbin Medical University, Harbin, Heilongjiang Province, China;
authors.forename: Sen
authors.initials: S
authors.lastname: Yan
authors.affiliation: Department of Cardiology, the First Affiliated Hospital, Harbin Medical University, Harbin, Heilongjiang Province, China;
authors.forename: Yue
authors.initials: Y
authors.lastname: Yuan
authors.affiliation: Department of Cardiology, the First Affiliated Hospital, Harbin Medical University, Harbin, Heilongjiang Province, China;
authors.forename: Dingyu
authors.initials: D
authors.lastname: Wang
authors.affiliation: Department of Cardiology, the First Affiliated Hospital, Harbin Medical University, Harbin, Heilongjiang Province, China;
authors.forename: Xue
authors.initials: X
authors.lastname: Ding
authors.affiliation: Department of Cardiology, the First Affiliated Hospital, Harbin Medical University, Harbin, Heilongjiang Province, China;
authors.forename: Guangzhong
authors.initials: G
authors.lastname: Liu
authors.affiliation: Department of Cardiology, the First Affiliated Hospital, Harbin Medical University, Harbin, Heilongjiang Province, China;
authors.forename: Wenpeng
authors.initials: W
authors.lastname: Li
authors.affiliation: Department of Cardiology, the First Affiliated Hospital, Harbin Medical University, Harbin, Heilongjiang Province, China;
authors.forename: Xuezhu
authors.initials: X
authors.lastname: Zhao
authors.affiliation: Department of Cardiology, the First Affiliated Hospital, Harbin Medical University, Harbin, Heilongjiang Province, China;
authors.forename: Zhaorui
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Department of Cardiology, the First Affiliated Hospital, Harbin Medical University, Harbin, Heilongjiang Province, China; Key Laboratory of Cardiac Diseases and Heart Failure, Harbin Medical University, Harbin, Heilongjiang Province, China; and ly99ly@vip.163.com.
authors.forename: Yue
authors.initials: Y
authors.lastname: Li
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000328:Adult; D000818:Animals; D001343:Autophagy / Q000187:drug effects; D002460:Cell Line; D002738:Chloroquine / Q000009:adverse effects; D006801:Humans; D006862:Hydrogen Sulfide / Q000097:blood; D015228:Hypertriglyceridemia / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D000960:Hypolipidemic Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D065626:Non-alcoholic Fatty Liver Disease / Q000139:chemically induced / Q000209:etiology / Q000517:prevention & control; D011446:Prospective Studies; D034622:RNA Interference; D011897:Random Allocation; D015398:Signal Transduction / Q000187:drug effects; D013440:Sulfides / Q000037:antagonists & inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D058570:TOR Serine-Threonine Kinases / Q000737:chemistry / Q000378:metabolism*
chemical_list: D000960:Hypolipidemic Agents; D013440:Sulfides; D002738:Chloroquine; C534978:Prkaa2 protein, mouse; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; C025451:sodium bisulfide; D006862:Hydrogen Sulfide
keywords: AMPK; NAFLD; autophagy; hydrogen sulfide; triglyceride