title: Amelioration of nonalcoholic fatty liver disease by hepatic stimulator substance via preservation of carnitine palmitoyl transferase-1 activity.
abstract: Nonalcoholic steatohepatitis (NASH) is the progressive form of nonalcoholic fatty liver disease and so far is supposed to be related with mitochondrial impairment. Hepatic stimulator substance (HSS) has been defined as a liver-protective factor promoting hepatocyte DNA synthesis and hepatic proliferation after liver intoxication. We previously reported that HSS ameliorated hepatocyte death, probably because of its preservation of mitochondria. This study aims to explore whether HSS could protect carnitine palmitoyl transferase-1 (CPT-1), an essential enzyme responsible for β-oxidation of free fatty acids in mitochondria, from lipotoxicity, thus alleviating hepatic lipid deposition. To test this, the HSS gene was delivered into C57BL/6J mice and efficiently expressed in the liver. NASH mice were prepared with high-fat diet or methionine-choline-deficient diet. The results showed that hepatic inflammation and liver functions were alleviated in the HSS-transfected mice; meanwhile, the activity of CPT-1 was obviously protected. Moreover, oleic acid (OA) treatment resulted in remarkable lipid accumulation in HepG2 cells; this deposition was improved by HSS transfection. Simultaneously, the CPT-1 activity, which was impaired by OA treatment, was profoundly rescued in the HSS-expressing cells. CPT-1 activity was more severely impaired if the OA treatment was combined with S15176, a CPT-1 inhibitor. However, this impairment was effectively reduced by the HSS transfection, and the effect was enhanced by C75, a CPT-1 activator. Interestingly, if the cells were transfected with HSS-siRNA, the preservation of CPT-1 provided by HSS was again diminished. In conclusion, HSS reduces lipotoxicity to mitochondria most likely via preservation of CPT-1.
authors.affiliation: Department of Cell Biology and Municipal Laboratory for Liver Protection and Regeneration Regulation, Capital Medical University, Beijing, China.
authors.forename: Weichun
authors.initials: W
authors.lastname: Xiao
authors.affiliation: Department of Cell Biology and Municipal Laboratory for Liver Protection and Regeneration Regulation, Capital Medical University, Beijing, China.
authors.forename: Meng
authors.initials: M
authors.lastname: Ren
authors.affiliation: Department of Cell Biology and Municipal Laboratory for Liver Protection and Regeneration Regulation, Capital Medical University, Beijing, China.
authors.forename: Can
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Department of Cell Biology and Municipal Laboratory for Liver Protection and Regeneration Regulation, Capital Medical University, Beijing, China.
authors.forename: Shenglan
authors.initials: S
authors.lastname: Li
authors.affiliation: Department of Cell Biology and Municipal Laboratory for Liver Protection and Regeneration Regulation, Capital Medical University, Beijing, China anwei@ccmu.edu.cn.
authors.forename: Wei
authors.initials: W
authors.lastname: An
mesh_terms: D000818:Animals; D002334:Carnitine O-Palmitoyltransferase / Q000378:metabolism*; D056945:Hep G2 Cells; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D065626:Non-alcoholic Fatty Liver Disease / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D010455:Peptides / Q000627:therapeutic use*
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; D010455:Peptides; C073456:hepatic stimulator substance; D002334:Carnitine O-Palmitoyltransferase
keywords: augmenter of liver regeneration; carnitine palmitoyl transferase-1; hepatic stimulator substance; methionine-choline-deficient diet; nonalcoholic steatohepatitis; oleic acid