Lipoprotein lipase activator ameliorates the severity of dietary steatohepatitis.
Dietary model of steatohepatitis was established by feeding mice a methionine choline deficient (MCD) diet. Mice on MCD or control diet for 3 weeks were treated with or without NO-1886, a newly synthetic lipoprotein lipase (LPL) activator. In a separate experiment, NO-1886 was given after pre-treatment with 3 weeks of MCD diet. NO-1886 significantly reduced MCD-induced inflammation by repressing levels of hepatic lipid peroxides and pro-inflammatory tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), and cyclooxygenase-2 (COX-2). In addition, NO-1886 dampened hepatic steatosis via accelerating fatty acid oxidation caused by enhanced expression of PPARalpha, cytochrome P450-10 (Cyp4a10), and Acyl-CoA oxidase (ACO). It failed to regulate genes of fatty acid uptake and synthesis pathways. In conclusion, NO-1886 ameliorated and induced regression of experimental steatohepatitis via increasing endogenous LPL activation resulting in suppression on pro-inflammatory factors and reduction of hepatic fatty acids. These findings indicate that NO-1886 is a potential therapeutic agent for steatohepatitis.
Yu
Jun
J
Institute of Digestive Disease, Department of Medicine and Therapeutics, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, NT, Hong Kong, China.
Chu
Eagle S H
ES
Hui
Alex Y
AY
Cheung
Kin F
KF
Chan
Henry L Y
HL
Leung
Wai K
WK
Farrell
Geoffrey C
GC
Sung
Joseph J Y
JJ
D000818:Animals; D001549:Benzamides / Q000008:administration & dosage / Q000494:pharmacology*; D002784:Cholesterol / Q000097:blood; D002796:Choline Deficiency; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D004032:Diet / Q000009:adverse effects; D004789:Enzyme Activation / Q000187:drug effects; D005234:Fatty Liver / Q000097:blood / Q000209:etiology / Q000517:prevention & control*; D015870:Gene Expression / Q000187:drug effects; D000960:Hypolipidemic Agents / Q000008:administration & dosage / Q000494:pharmacology; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D050155:Lipogenesis / Q000235:genetics; D008071:Lipoprotein Lipase / Q000235:genetics / Q000378:metabolism*; D008075:Lipoproteins, HDL / Q000097:blood; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D008715:Methionine / Q000172:deficiency; D051379:Mice; D008810:Mice, Inbred C57BL; D009943:Organophosphorus Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
D001549:Benzamides; D000960:Hypolipidemic Agents; D015850:Interleukin-6; D008075:Lipoproteins, HDL; D009943:Organophosphorus Compounds; D047495:PPAR gamma; D012333:RNA, Messenger; D017392:Thiobarbituric Acid Reactive Substances; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1; C082137:4-diethoxyphosphorylmethyl-N-(4-bromo-2-cyanophenyl)benzamide; D002784:Cholesterol; D008715:Methionine; D051546:Cyclooxygenase 2; D008071:Lipoprotein Lipase