title: Microarray analysis of gene expression in liver, adipose tissue and skeletal muscle in response to chronic dietary administration of NDGA to high-fructose fed dyslipidemic rats.
abstract: Nordihydroguaiaretic acid (NDGA), the main metabolite of Creosote Bush, has been shown to have profound effects on the core components of metabolic syndrome, including lowering of blood glucose, free fatty acids and triglyceride levels, attenuating elevated blood pressure in several rodent models of dyslipidemia, and improving body weight, insulin resistance, diabetes and hypertension. In the present study, a high-fructose diet fed rat model of hypertriglyceridemia, dyslipidemia, insulin resistance and hepatic steatosis was employed to investigate the global transcriptional changes in the lipid metabolizing pathways in three insulin sensitive tissues: liver, skeletal muscle and adipose tissue in response to chronic dietary administration of NDGA. Sprague-Dawley male rats (SD) were fed a chow (control) diet, high-fructose diet (HFrD) or HFrD supplemented with NDGA (2.5 g/kg diet) for eight weeks. Dietary administration of NDGA decreased plasma levels of TG, glucose, and insulin, and attenuated hepatic TG accumulation. DNA microarray expression profiling indicated that dietary administration of NDGA upregulated the expression of certain genes involved in fatty acid oxidation and their transcription regulator, PPARα, decreased the expression of a number of lipogenic genes and relevant transcription factors, and differentially impacted the genes of fatty acid transporters, acetyl CoA synthetases, elongases, fatty acid desaturases and lipid clearance proteins in liver, skeletal muscle and adipose tissues. These findings suggest that NDGA ameliorates hypertriglyceridemia and steatosis primarily by inhibiting lipogenesis and enhancing fatty acid catabolism in three major insulin responsive tissues by altering the expression of key enzyme genes and transcription factors involved in de novo lipogenesis and fatty acid oxidation.
authors.affiliation: Geriatric Research, Education and Clinical Center, VA Palo Alto Health Care System, Palo Alto, CA USA ; Division of Endocrinology, Stanford University, Stanford, CA USA ; Present Address: Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033 USA.
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, CA USA ; Division of Endocrinology, Stanford University, Stanford, CA USA.
authors.forename: Wen-Jun
authors.identifier: 0000-0001-5150-1698
authors.initials: WJ
authors.lastname: Shen
authors.affiliation: Geriatric Research, Education and Clinical Center, VA Palo Alto Health Care System, Palo Alto, CA USA ; Division of Endocrinology, Stanford University, Stanford, CA USA ; Present Address: Department of Pediatrics, Saint Louis University School of Medicine, St. Louis, MO USA.
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, CA USA.
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, CA USA.
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, CA USA.
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, CA USA.
authors.forename: Yuan F
authors.initials: YF
authors.lastname: Cortez
authors.affiliation: Geriatric Research, Education and Clinical Center, VA Palo Alto Health Care System, Palo Alto, CA USA ; Division of Endocrinology, Stanford University, Stanford, CA USA.
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, CA USA ; Division of Endocrinology, Stanford University, Stanford, CA USA.
authors.forename: Salman
authors.initials: S
authors.lastname: Azhar
keywords: CD36; Fatty acid oxidation; Hypertriglyceridemia; L-FABP; Lipogenesis; Malony-CoA decarboxylase; Steatosis