Nordihydroguaiaretic acid, a lignan from Larrea tridentata (Creosote bush) protects against ALIOS diet-induced metabolic dysfunction in mice. The Journal of pharmacology and experimental therapeutics Chan, J. K., Bittner, S. n., Bittner, A. n., Atwal, S. n., Shen, W. J., Inayathullah, M. n., Rajada, J. n., Nicolls, M. R., Kraemer, F. B., Azhar, S. n. 2018


To determine the effects of NDGA on metabolic and molecular changes in response to feeding mice typical American fast food or Western diet, mice were fed with ALIOS diet and subjected to metabolic analysis. Male C57BL/6J mice were randomly assigned to: ALIOS, ALIOS + NDGA, or control diet and maintained on the specific diet for 8 weeks. Mice fed ALIOS diet, showed increased body, liver and epididymal fat pad weight, plasma ALT and AST levels (a measure of liver injury), and liver triglyceride (TG) content. Co-administration of NDGA normalized body and epididymal fat pad weight, ALT and AST levels, and liver TG. NDGA treatment also improved insulin sensitivity but not glucose intolerance in ALIOS diet fed mice. In ALIOS diet fed mice, NDGA supplementation induced PPARa (the master regulator of fatty acid oxidation) and mRNA levels of Cpt1c and Cpt2, key genes involved in fatty acid oxidation as compared to ALIOS diet. NDGA significantly reduced liver ER stress response CHOP protein, as compared to chow or ALIOS diet and also ameliorated ALIOS diet-induced elevation of apoptosis signaling protein, CASP3. Likewise, NDGA downregulated the ALIOS-diet induced mRNA levels of Pparg, Fasn, and Dgat2. NDGA treatment of ALIOS fed mice upregulated the hepatic expression of antioxidant enzymes, GPX4 and PRDX3 proteins. In conclusion, we provide evidence that NDGA improves metabolic dysregulation by simultaneously modulating PPARa transcription factor and key genes involved in fatty acid oxidation, key antioxidant and lipogenic enzymes, and apoptosis and ER stress signaling pathways.

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