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.

Nordihydroguaiaretic Acid, a Lignan fromLarrea tridentata(Creosote Bush), Protects Against American Lifestyle-Induced Obesity Syndrome Diet–Induced Metabolic Dysfunction in Mice

“…A short-term (4 days) NDGA treatment attenuated hyperinsulinemia, and fasting plasma glucose and NEFA levels. Analysis of HOMA-IR further confirmed that NDGA treatment ameliorated insulin resistance induced by feeding a high-fructose diet (Zhang et al, 2015). In contrast, we reported previously that NDGA treatment improved both glucose intolerance and insulin sensitivity in ob/ob mice (Zhang et al, 2013).…”

“…However, feeding mice ALIOS diet supplemented with NDGA improved insulin sensitivity, but mice (Zhang et al, 2015). A short-term (4 days) NDGA treatment attenuated hyperinsulinemia, and fasting plasma glucose and NEFA levels.…”

“…Previous studies from this laboratory have shown that nordihydroguaiaretic acid (NDGA), one of the major constituents of Creosote bush, Larrea tridentata, exerts profound effects on a number of metabolic abnormalities, including improving obesity, dyslipidemia, insulin resistance, hypertension, steatosis, and altered glucose metabolism, in several rodent models (Zhang et al, 2013(Zhang et al, , 2015(Zhang et al, , 2016. Although these studies provided important mechanistic information by which NDGA improves metabolic abnormalities, they were carried out mainly using genetically manipulated (e.g.…”

Anti‐hyperlipidaemic effects of synthetic analogues of nordihydroguaiaretic acid in dyslipidaemic rats

“…No validated therapies for NAFLD currently exist (Barb et al ., ). Previous studies from this laboratory have shown that nordihydroguaiaretic acid (NDGA , also called masoprocol), the active ingredient of the folk medicinal plant, Creosote bush (Arteaga et al ., ), exerts profound effects on several components of the metabolic syndrome, including lowering blood glucose, FFAs, and TG levels and attenuating elevated BP in several rodent models of dyslipidaemia, insulin resistance and hypertension (Gowri et al ., ,b, ; Scribner et al ., ; Zhang et al ., , , ). Previously, we provided evidence that the beneficial actions of NDGA on dyslipidaemia and hepatic steatosis in ob/ob mice are exerted primarily through enhanced fatty acid oxidation via PPARα ‐dependent pathways (Zhang et al ., ).…”

“…Previously, we provided evidence that the beneficial actions of NDGA on dyslipidaemia and hepatic steatosis in ob/ob mice are exerted primarily through enhanced fatty acid oxidation via PPARα ‐dependent pathways (Zhang et al ., ). More recently, we reported that both acute and chronic treatment of high‐fructose diet (HFrD) fed dyslipidaemic rats ameliorates hypertriglyceridaemia and hepatic steatosis primarily by promoting increased channelling of fatty acids towards their β‐oxidation and interfering with lipogenesis (Zhang et al ., , ).…”