|Nordihydroguaiaretic acid improves metabolic dysregulation and aberrant hepatic lipid metabolism in mice by both PPARα-dependent and -independent pathways.|
|PMID: 23104557 Owner: NLM Status: MEDLINE|
|Creosote bush-derived nordihydroguaiaretic acid (NDGA), a lipoxygenase inhibitor, possesses antioxidant properties and functions as a potent antihyperlipidemic agent in rodent models. Here, we examined the effect of chronic NDGA treatment of ob/ob mice on plasma dyslipidemia, hepatic steatosis, and changes in hepatic gene expression. Feeding ob/ob mice a chow diet supplemented with either low (0.83 g/kg diet) or high-dose (2.5 g/kg diet) NDGA for 16 wk significantly improved plasma triglyceride (TG), inflammatory chemokine levels, hyperinsulinemia, insulin sensitivity, and glucose intolerance. NDGA treatment caused a marked reduction in liver weight and TG content, while enhancing rates of fatty acid oxidation. Microarray analysis of hepatic gene expression demonstrated that NDGA treatment altered genes for lipid metabolism, with genes involved in fatty acid catabolism most significantly increased. NDGA upregulated the mRNA and nuclear protein levels of peroxisome proliferator-activated receptor α (PPARα), and the activated (phosphorylated) form of AMP-activated kinase. NDGA increased PPARα promoter activity in AML12 hepatocytes and also prevented the fatty acid suppression of PPARα expression. In contrast, PPARα siRNA abrogated the stimulatory effect of NDGA on fatty acid catabolism. Likewise, no stimulatory effect of NDGA on hepatic fatty acid oxidation was observed in the livers of PPARα-deficient mice, but the ability of NDGA to reverse fatty liver conditions was unaffected. In conclusion, the beneficial actions of NDGA on dyslipidemia and hepatic steatosis in ob/ob mice are exerted primarily through enhanced fatty acid oxidation via PPARα-dependent pathways. However, PPARα-independent pathways also contribute to NDGA's action to ameliorate hepatic steatosis.|
|Haiyan Zhang; Wen-Jun Shen; Yuan Cortez; Fredric B Kraemer; Salman Azhar|
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|Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, U.S. Gov't, Non-P.H.S. Date: 2012-10-25|
|Title: American journal of physiology. Gastrointestinal and liver physiology Volume: 304 ISSN: 1522-1547 ISO Abbreviation: Am. J. Physiol. Gastrointest. Liver Physiol. Publication Date: 2013 Jan|
|Created Date: 2013-01-02 Completed Date: 2013-02-20 Revised Date: 2014-01-09|
Medline Journal Info:
|Nlm Unique ID: 100901227 Medline TA: Am J Physiol Gastrointest Liver Physiol Country: United States|
|Languages: eng Pagination: G72-86 Citation Subset: IM|
|APA/MLA Format Download EndNote Download BibTex|
Endoplasmic Reticulum Stress / physiology
Endoribonucleases / metabolism
Fatty Acids / metabolism
Fatty Liver / drug therapy
Glucose Tolerance Test
Hypolipidemic Agents / therapeutic use*
Leptin / deficiency
Lipid Metabolism / genetics
Lipid Metabolism Disorders / drug therapy*
Lipoproteins, VLDL / metabolism
Lipoxygenase Inhibitors / therapeutic use*
Liver / drug effects, metabolism*
Masoprocol / therapeutic use*
Mice, Inbred C57BL
PPAR alpha / physiology*
Protein-Serine-Threonine Kinases / metabolism
Real-Time Polymerase Chain Reaction
Signal Transduction / drug effects
Triglycerides / biosynthesis
|1R01HL92473/HL/NHLBI NIH HHS|
|0/Adipokines; 0/Fatty Acids; 0/Hypolipidemic Agents; 0/Leptin; 0/Lipoproteins, VLDL; 0/Lipoxygenase Inhibitors; 0/PPAR alpha; 0/Triglycerides; 7BO8G1BYQU/Masoprocol; EC 188.8.131.52/Ern1 protein, mouse; EC 184.108.40.206/Protein-Serine-Threonine Kinases; EC 3.1.-/Endoribonucleases|
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