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.
Highlights
Nonalcoholic fatty liver disease (NAFLD), the most common cause of chronic liver disease [1,2,3], is a major health problem worldwide [2, 4]
Effect of chronic dietary Nordihydroguaiaretic acid (NDGA) treatment on physical and metabolic characteristics of high-fructose diet fed rats We examined the effects of chronic dietary NDGA treatment on hypertriglyceridemia and hepatic steatosis, and profiled by microarray analysis the expression of enzymes and regulatory proteins involved in lipid metabolism of three insulin-sensitive tissues liver, skeletal muscle and adipose tissue
The groups of rats were maintained on a control chow diet, high-fructose diet (HFrD) or HFrD supplemented with 2.5 g NDGA/kg diet (HFrDNDGA) (~94 mg/kg BW/24 h) for 16 weeks and, subsequently, liver, mixed gastrocnemius muscle and white adipose tissue samples were subjected to Gene Microarray Analysis
Summary
Nonalcoholic fatty liver disease (NAFLD), the most common cause of chronic liver disease [1,2,3], is a major health problem worldwide [2, 4]. During the past few decades, the prevalence and severity of NAFLD have been paralleled with that of obesity, type 2 diabetes and metabolic syndrome (MetS) [4, 11, 12] and many studies have reported a pathophysiologic association between NAFLD and these disorders [11,12,13,14,15,16,17,18]. MetS is the umbrella description given to a number of derangements including insulin resistance and glucose intolerance, Zhang et al Nutrition & Metabolism (2016) 13:63. NAFLD is closely tied to insulin resistance and hepatic dyslipidemia and is considered as a hepatic manifestation of MetS [12, 14,15,16,17]. There are no designated therapies in the clinical management of NAFLD except lifestyle modification including weight reduction, diet and exercise, which are hard to comply with on a long-term schedule [25,26,27]
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