Salman Azhar, PhD, Associate Director for Research, GRECC, VA Palo Alto Health Care System; Adjunct Professor of Medicine (Endocrinology), Stanford University School of Medicine
Research Description: Dr. Azhar’s group investigates small molecules as potential drugs to treat metabolic syndrome (MetS) nonalcoholic fatty liver disease (NAFLD, a hepatic manifestation of MetS) and associated diabetes complications. For example, we have shown that nordihydroguaiaretic acid (NDGA) has a profound ameliorative effect on the core components of MetS, including lowering triglyceride levels and attenuating elevated blood pressure in rodent models, leading to improved obesity, insulin resistance, diabetes and hepatic steatosis. Our recent work suggests that NDGA exerts its hypolipidemic actions primarily by stimulating the activity of PPARalpha, the master regulator of hepatic fatty acid oxidation systems, which, in turn, improves dyslipidemia by promoting increased channeling of fatty acids towards their oxidation and thereby restricting production, storage and secretion of VLDL-TG. These data are supported by our demonstration that administration of NDGA to mouse and rat models of insulin resistance, dyslipidemia and hepatic steatosis leads to robust induction of two downstream targets of PPARα, CD36 (fatty acid transporter) and liver fatty-acid–binding protein. Additional studies are underway to further explore the underlying mechanisms by which NDGA exerts its beneficial action particularly on dyslipidemia. Dr. Azhar’s group has long-standing, productive collaborations with Stanford DRC members listed below.
Selected relevant publications (Stanford DRC members in BOLD):
1. Zhang H, Shen W-J, Cortez Y, Kraemer FB, Azhar S. 2013. Nordihydroguaiaretic acid implroves metabolic dysregulation and aberrant hepatic lipid metabolism in mice by both PPAR–dependent and –independent pathways. Am J Physiol Gastrointest Liv Physiol 304(1): G72-86.
2. Ueno M, Shen W-J, Patel S, Greenberg AS, Azhar S, Kraemer FB. 2013. Fat specific protein 27 modulates nuclear factor of activated-T cells 5 and cellular response to stress. J Lipid Res 54(3): 734-43.
3. Kan CFK, Singh AB, Stafforin DM, Azhar S, and Liu J. 2014. Arachidonic acid down regulates acyl-CoA synthetase 4 expression by promoting its ubiquitination and proteasomal degradation. J Lipid Res 55: 1657-1667.
4. Dong B, Singh AB, Azhar S, Nabil NG, Liu J. 2015. High-fructose feeding promotes accelerated degradation of hepatic LDL receptor and hypercholesterolemia in hamsters via elevated circulating PCSK9 levels. Atherosclerosis 239: 364-374.
5. Helenius TO, Misiorek JO, Nyström JH, Fortelius LE, Habtezion A, Liao J, Asghar MN, Zhang H, Azhar S, Omary MB, Toivola DM. 2015. Keratin 8 absence downregulates colonocyte HMGCS2 and modulates colonocyte energy metabolism. Mol BiolCell 26: 2298-2320.
6. Zhang H, Shen W-J, Li Y, Bittner A, Bittner S, Tabassum J, Cortez YF, Kraemer FB, Azhar S. 2016. 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. Nutr Metab (Lond).13: 63.