title: Effect of Creosote Bush-Derived NDGA on Expression of Genes Involved in Lipid Metabolism in Liver of High-Fructose Fed Rats: Relevance to NDGA Amelioration of Hypertriglyceridemia and Hepatic Steatosis.
abstract: Nordihydroguaiaretic acid (NDGA), the main metabolite of Creosote bush, has been shown to have profound effects on the core components of the metabolic syndrome (MetS), lowering blood glucose, free fatty acids (FFA) and triglyceride (TG) levels in several models of dyslipidemia, as well as improving body weight (obesity), insulin resistance, diabetes and hypertension, and ameliorating hepatic steatosis. In the present study, a high-fructose diet (HFrD) fed rat model of hypertriglyceridemia was employed to further delineate the underlying mechanism by which NDGA exerts its anti-hypertriglyceridemic action. In the HFrD treatment group, NDGA administration by oral gavage decreased plasma levels of TG, glucose, FFA, and insulin, increased hepatic mitochondrial fatty acid oxidation and attenuated hepatic TG accumulation. qRT-PCR measurements indicated that NDGA treatment increased the mRNA expression of key fatty acid transport (L-FABP, CD36), and fatty acid oxidation (ACOX1, CPT-2, and PPARα transcription factor) genes and decreased the gene expression of enzymes involved in lipogenesis (FASN, ACC1, SCD1, L-PK and ChREBP and SREBP-1c transcription factors). Western blot analysis indicated that NDGA administration upregulated hepatic insulin signaling (P-Akt), AMPK activity (P-AMPK), MLYCD, and PPARα protein levels, but decreased SCD1, ACC1 and ACC2 protein content and also inactivated ACC1 activity (increased P-ACC1). These findings suggest that NDGA ameliorates hypertriglyceridemia and hepatic steatosis primarily by interfering with lipogenesis and promoting increased channeling of fatty acids towards their oxidation.
authors.affiliation: Geriatric Research, Education and Clinical Center, VA Palo Alto Health Care System, Palo Alto, California, United States of America; Division of Endocrinology, Stanford University, Stanford, California, United States of America.
authors.forename: Haiyan
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Geriatric Research, Education and Clinical Center, VA Palo Alto Health Care System, Palo Alto, California, United States of America; Division of Endocrinology, Stanford University, Stanford, California, United States of America.
authors.forename: Yihang
authors.initials: Y
authors.lastname: Li
authors.affiliation: Geriatric Research, Education and Clinical Center, VA Palo Alto Health Care System, Palo Alto, California, United States of America.
authors.forename: Jie
authors.initials: J
authors.lastname: Hu
authors.affiliation: Geriatric Research, Education and Clinical Center, VA Palo Alto Health Care System, Palo Alto, California, United States of America; Division of Endocrinology, Stanford University, Stanford, California, United States of America.
authors.forename: Wen-Jun
authors.initials: WJ
authors.lastname: Shen
authors.affiliation: Geriatric Research, Education and Clinical Center, VA Palo Alto Health Care System, Palo Alto, California, United States of America; Division of Endocrinology, Stanford University, Stanford, California, United States of America.
authors.forename: Madhurima
authors.initials: M
authors.lastname: Singh
authors.affiliation: Geriatric Research, Education and Clinical Center, VA Palo Alto Health Care System, Palo Alto, California, United States of America; Division of Endocrinology, Stanford University, Stanford, California, United States of America.
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Hou
authors.affiliation: Geriatric Research, Education and Clinical Center, VA Palo Alto Health Care System, Palo Alto, California, United States of America.
authors.forename: Alex
authors.initials: A
authors.lastname: Bittner
authors.affiliation: Geriatric Research, Education and Clinical Center, VA Palo Alto Health Care System, Palo Alto, California, United States of America.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Bittner
authors.affiliation: Geriatric Research, Education and Clinical Center, VA Palo Alto Health Care System, Palo Alto, California, United States of America.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Cortez
authors.affiliation: Geriatric Research, Education and Clinical Center, VA Palo Alto Health Care System, Palo Alto, California, United States of America.
authors.forename: Juveria
authors.initials: J
authors.lastname: Tabassum
authors.affiliation: Geriatric Research, Education and Clinical Center, VA Palo Alto Health Care System, Palo Alto, California, United States of America; Division of Endocrinology, Stanford University, Stanford, California, United States of America.
authors.forename: Fredric B
authors.initials: FB
authors.lastname: Kraemer
authors.affiliation: Geriatric Research, Education and Clinical Center, VA Palo Alto Health Care System, Palo Alto, California, United States of America; Division of Endocrinology, Stanford University, Stanford, California, United States of America.
authors.forename: Salman
authors.initials: S
authors.lastname: Azhar
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000103:Acetyl-CoA Carboxylase / Q000235:genetics / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D050556:Fatty Acid-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005234:Fatty Liver / Q000097:blood / Q000139:chemically induced / Q000517:prevention & control*; D005632:Fructose / Q000008:administration & dosage / Q000633:toxicity; D005786:Gene Expression Regulation / Q000187:drug effects*; D015228:Hypertriglyceridemia / Q000097:blood / Q000139:chemically induced / Q000517:prevention & control*; D032442:Larrea / Q000737:chemistry*; D050356:Lipid Metabolism / Q000235:genetics*; D050155:Lipogenesis / Q000235:genetics; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D009637:Masoprocol / Q000494:pharmacology*; D047493:PPAR alpha / Q000235:genetics / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics / Q000378:metabolism
chemical_list: C493321:Fabp1 protein, rat; D050556:Fatty Acid-Binding Proteins; D047493:PPAR alpha; D051780:Sterol Regulatory Element Binding Protein 1; D005632:Fructose; D009637:Masoprocol; D055372:AMP-Activated Protein Kinases; D000103:Acetyl-CoA Carboxylase