My laboratory uses molecular biological and genomic approaches to study hormonal regulation of transcription, particularly thyroid hormone (TH). We study whether epigenetic changes such as DNA methylation and histone modifications play a role in positive and negative regulation of transcription, endocrine tumors, long-term suppression of negative feedback by TH, and hormone-responsiveness during aging. Recently, we have shown that TH regulates Fox01 via SIRT deacetylation to regulate gluconeogenic genes, and we currently are studying this novel regulatory mechanism in greater detail. We also examine the potential beneficial effects and mechanisms of TH on non-alcoholic fatty liver disease (NAFLD), a common complication of obesity and diabetes. My laboratory’s recent discovery that TH as well as other hormones and compounds such as caffeine and epigallocatechin-3-gallate (EGCG) can induce autophagy coupled with increased b-oxidation of fatty acid has suggested novel potential therapeutic strategies for this condition. I also have initiated a clinical study examining whether levothyroxine can ameliorate hepatosteatosis and glucose control in diabetic Asian patients in patients with NAFLD. I have collaborated with Dr. Dwight Koeberl, Duke University for the past two years to examine the role of autophagy in the hepatosteatosis and hepatic glycogen storage in G6Pase deficiency. We have found that there is defective autophagy, impaired beta oxidation of fatty acids, and mitochondrial injury and dysfunction in G6Pase deficiency suggesting that correction of the autophagy defect can improve the major hepatic metabolic dysfunctions in this disease.
1. Sinha RA, You SH, Zhou J, Siddique MM, Bay BH, Zhu X, Privalsky ML, Cheng SY, Stevens RD, Summers SA, Newgard CB, Lazar MA, Yen PM. Thyroid hormone stimulates hepatic lipid catabolism via activation of autophagy. J Clin Invest. 2012; 122:2428-38.
2. Wang G, Cao X, Lai S, Luo X, Feng Y, Xia X, Yen PM, Gong J, Hu J. PI3K stimulates DNA synthesis and cell-cycle progression via its p55PIK regulatory subunit interaction with PCNA. Mol Cancer Ther 2013; 12(10):2100-9.
3. Sinha RA, Farah BL, Singh BK, Siddique MM, Li Y, Wu Y, Ilkayeva OR, Gooding J, Ching J, Zhou J, Martinez L, Xie S, Bay BH, Summers SA, Newgard CB, Yen PM. Caffeine stimulates hepatic lipid metabolism via autophagy-lysosomal pathway. Hepatology. 2013 Aug 8. doi: 10.1002/hep.26667.
4. Singh BK, Sinha RA, Zhou J, Xie SY, You SH, Gauthier K, Yen PM. FoxO1-deacetylation regulates thyroid hormone induced transcription of key hepatic gluconeogenic genes. J Biol Chem 2013; 288:30365-72.
5. Yap CS, Sinha RA, Ota S, Katsuki M, Yen PM. Thyroid hormone negatively regulates CDX2 and SOAT2 mRNA expression via induction of miRNA-181d in hepatic cells. Biochem Biophys Res Commun. 2013; 440:635-9.
6. Xie SY, Sinha RA, Singh BK, Li GD, Han W, Yen PM. Resveratrol induces insulin gene expression in mouse pancreatic α-cells. Cell Biosci 2013; 3:47.
7. Zhou J, Farah BL, Sinha RA, WuY, Singh BK, Bay B-H, Yang CS, Yen PM. Epigallocatechin-3-gallate (EGCG), a green tea polyphenol, stimulates hepatic autophagy and lipid clearance. PLOS One 2014; 9;8761
8. Aw DKL, Sinha RA, Tan HC, Loh LM, Salvatore D, Yen PM. Consumptive hypothyroidism due to sonic hedgehog pathway activation of deiodinase 3. J Clin Endo Metab 2014; 99:3965-71.9. Farah BL, Madden L, Li S, Nance S, Bird A, Bursac N, Yen PM, Young SP, Koeberl DD. Adjunctive b2-agonist treatment reduces glycogen independent of receptor-mediated acid -glucosidase uptake in the limb muscles of mice with Pompe disease. FASEB Journal; 2014 28:2272-80.10. Aw DKL, Sinha RA, Xie SY, Yen PM. Glucagon inhibits insulin signaling in hepatic cells via a novel PKA-AMPK-mTORC1 pathway. Biochem Biophys Res Commun 2013; 440:635-9.11. Farah BL, Sinha RA, Wu Y, Singh BK, Zhou J, Bay BH, Yen PM. b-Adrenergic agonist and antagonist regulation of hepatic autophagy. PLOS One 2014; 9:e98155.12. Zhou J, Yap CS, Ang C, Vijayaraghavan A, Xiu S, Wan WK, Tan I, Tan P, Lim K-H, Yen PM, Goh LK. Multi-regulated gene analysis identifies DDX27 a novel oncogenic protein in gastric cancer causing epirubicin resistance. Carcinogenesis 2015; 36:441-51. 13. Sinha RA, Singh BK, Zhou J, Wu Y, Farah BL, Ohba,K, Lesmana R, Gooding J, Bay BH, Yen PM. Thyroid hormone induction of mitochondrial activity is coupled to mitophagy via ROS-AMPK-ULK1 signaling. Autophagy 2015; 11(8):1341-57 14. Singh BK, Sinha RA, Zhou J, Tripathi M, Ohba K, Wang ME, Astapova I, Ghosh S, Hollenberg AN, Gauthier K, Yen PM. Hepatic FOXO1 target genes are co-regulated by thyroid hormone via RICTOR deacetylation and MTORC2-AKT inhibition. J Biol Chem 2015; In Press. 15. Farah BL, Landau DJ, Sinha RA, Brooks ED, Wu Y, Fung SY, Tanaka T, Hirayama M, Bay BH, Koeberl DD, Yen PM. Induction of autophagy improves hepatic lipid metabolism in glucose-6-phosphatase deficiency. J Hepatol 2015; In Press. 16. Lesmana R, Singh BK, Sinha RA, Zhou J, Tripathi M, Ohba K, Yajun Wu Y, Yau WY, Bay BH, Yen, PM. Thyroid hormone stimulation of autophagy is essential for mitochondrial biogenesis and activity in skeletal muscle. Endocrinology 2015; In Press.
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