title: Nordihydroguaiaretic acid improves metabolic dysregulation and aberrant hepatic lipid metabolism in mice by both PPARα-dependent and -independent pathways.
abstract: 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.
authors.affiliation: Geriatric Research, Education and Clinical Center, VA Palo Alto Health Care System, Palo Alto, CA 94304, USA.
authors.forename: Haiyan
authors.initials: H
authors.lastname: Zhang
authors.forename: Wen-Jun
authors.initials: WJ
authors.lastname: Shen
authors.forename: Yuan
authors.initials: Y
authors.lastname: Cortez
authors.forename: Fredric B
authors.initials: FB
authors.lastname: Kraemer
authors.forename: Salman
authors.initials: S
authors.lastname: Azhar
mesh_terms: D054392:Adipokines / Q000378:metabolism; D000818:Animals; D004032:Diet; D059865:Endoplasmic Reticulum Stress / Q000502:physiology; D004722:Endoribonucleases / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism; D005234:Fatty Liver / Q000188:drug therapy; D005951:Glucose Tolerance Test; D000960:Hypolipidemic Agents / Q000627:therapeutic use*; D020738:Leptin / Q000172:deficiency; D050356:Lipid Metabolism / Q000235:genetics; D052439:Lipid Metabolism Disorders / Q000188:drug therapy*; D008079:Lipoproteins, VLDL / Q000378:metabolism; D016859:Lipoxygenase Inhibitors / Q000627:therapeutic use*; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D009637:Masoprocol / Q000627:therapeutic use*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D046228:Microarray Analysis; D005810:Multigene Family; D047493:PPAR alpha / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D014280:Triglycerides / Q000096:biosynthesis
chemical_list: D054392:Adipokines; D005227:Fatty Acids; D000960:Hypolipidemic Agents; D020738:Leptin; D008079:Lipoproteins, VLDL; D016859:Lipoxygenase Inhibitors; D047493:PPAR alpha; D014280:Triglycerides; D009637:Masoprocol; C510185:Ern1 protein, mouse; D017346:Protein Serine-Threonine Kinases; D004722:Endoribonucleases