Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Benzamides / administration & dosage
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Benzamides / pharmacology*
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Cholesterol / blood
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Choline Deficiency
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Cyclooxygenase 2 / genetics
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Cyclooxygenase 2 / metabolism
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Diet / adverse effects
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Enzyme Activation / drug effects
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Fatty Liver / blood
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Fatty Liver / etiology
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Fatty Liver / prevention & control*
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Gene Expression / drug effects
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Hypolipidemic Agents / administration & dosage
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Hypolipidemic Agents / pharmacology
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Intercellular Adhesion Molecule-1 / genetics
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Intercellular Adhesion Molecule-1 / metabolism
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Interleukin-6 / genetics
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Interleukin-6 / metabolism
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Lipogenesis / genetics
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Lipoprotein Lipase / genetics
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Lipoprotein Lipase / metabolism*
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Lipoproteins, HDL / blood
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Liver / drug effects
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Liver / metabolism
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Liver / pathology
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Male
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Methionine / deficiency
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Mice
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Mice, Inbred C57BL
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Organophosphorus Compounds / administration & dosage
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Organophosphorus Compounds / pharmacology*
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PPAR gamma / genetics
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PPAR gamma / metabolism
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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Thiobarbituric Acid Reactive Substances / metabolism
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Tumor Necrosis Factor-alpha / genetics
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Tumor Necrosis Factor-alpha / metabolism
Substances
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Benzamides
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Hypolipidemic Agents
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Interleukin-6
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Lipoproteins, HDL
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Organophosphorus Compounds
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PPAR gamma
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RNA, Messenger
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Thiobarbituric Acid Reactive Substances
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Tumor Necrosis Factor-alpha
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Intercellular Adhesion Molecule-1
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4-diethoxyphosphorylmethyl-N-(4-bromo-2-cyanophenyl)benzamide
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Cholesterol
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Methionine
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Cyclooxygenase 2
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Lipoprotein Lipase