Sayeepriyadarshini "Sayee" Anakk

anakk@illinois.edu

453 Medical School Building
Office: (217) 300-7905
Fax: (217) 244-5858

Lab Page

Sayeepriyadarshini "Sayee" Anakk

Assistant Professor of Molecular and Integrative Physiology

Research Topics

Endocrinology, Metabolic Regulation, Regulation of Gene Expression

Education

Bachelors in Pharmacy, Birla Institute of Technology & Sciences, Pilani, India
MSc, Birla Institute of Technology & Sciences, Pilani, India (Biological Sciences)
Ph.D., University of Texas, Graduate School of Biomedical Sciences at Houston (Biochemistry)
Postdoctoral Fellow, Baylor College of Medicine, Houston

Teaching Interests

Liver metabolism in normal and diseased state

My laboratory will focus on understanding liver metabolism in normal and diseased state. Our goal is to investigate how bile acids and nuclear receptors maintain metabolic homeostasis, and contribute to liver diseases, including cancer using cell-based systems and genetically engineered mouse models.

Liver is a major organ that regulates metabolism of triglycerides, cholesterol, glucose, amino acids, heme, xenobiotics and many more substances. One of the salient features of the liver is to make bile! Bile acids are amphiphilic detergents synthesized in liver to facilitate absorption of dietary lipids. Biliary homeostasis is critical and defects/dysfunctions in this pathway lead to several liver diseases including liver cancer.

Nuclear receptor signaling regulates biliary homeostasis.

Bile acid concentrations are tightly maintained through a negative feedback mechanisms coordinated chiefly by nuclear receptors, Farnesoid X Receptor (FXR) and Small Heterodimer Partner (SHP). We generated global FXR; SHP double knockout (DKO) mice to understand the consequence of biliary overload. These DKO mice have chronically elevated bile acids and mimic pediatric cholestasis.

We next want to examine the tissue specific role for FXR and SHP. Is the coordinate role of FXR and SHP observed in liver maintained in other tissues as well? How does tissue specific loss of these two receptors affect synthesis, transport and recirculation of bile acids?

Nuclear receptor signaling regulates adipogenesis

Obesity and diabetes have emerged as major epidemics of the 21st century. More than 100 genes have now been identified for their role in regulating body fat. These genes are controlled by multiple signals, including nuclear receptors and bile acids (BAs).

Our findings indicate that elevated BAs protect against obesity. It is fascinating that naïve mice on a BA enriched diet as well as DKO mice, which have elevated BAs, exhibit decreased visceral fat without any difference in food intake. We want to understand how BAs and nuclear receptors, especially FXR and SHP, regulate this beneficial effect. Do they burn more fat? Are they more active? Do they have defective adipogenesis?

Bile acids signal to Hippo pathway and cause hepatocellular carcinoma (HCC)

HCC is the fifth most common malignancy and results in 500,000 deaths annually. The underlying molecular events leading to HCC are still being evaluated and no targeted drug therapy currently exists for HCC.

Hippo signaling has been recently identified as a regulator of organ size and as a critical contributing factor to the development of spontaneous HCC. Bile acids are known to promote liver tumors and we recently identified BAs as regulators of hippo pathway. Consistent with this, the DKO mice, which have excess amounts of BAs develop rigorous and spontaneous HCC. We are excited to examine the importance of BA mediated YAP activation in liver tumorigenesis. How do BAs signal to the hippo pathway? Is it direct or mediated via other signaling proteins? Is there any nuclear receptor involved in this process?

Overall, these projects will broaden our understanding of bile acid signaling and nuclear receptor-mediated pathways necessary in the maintenance of energy balance, regulation of hepatic metabolism, and protection from tumorigenesis.

Awards

2016 - Outstanding Advisor Award, Medical Scholars Program, UIUC, IL

Representative Publications

1. Akinrotimi O, Riessen R, VanDuyne P, Park JE, Lee YK, Wong LJ, Zavacki AM, Schoonjans K, Anakk S. (2017) Shp deletion prevents hepatic steatosis and when combined with Fxr loss protects against type 2 diabetes. Hepatology. doi: 10.1002/hep.29305.

2. Kim KH, Choi S, Zhou Y, Kim EY, Lee JM, Saha PK, Anakk S, Moore DD. (2017) Hepatic FXR/SHP axis modulates systemic glucose and fatty acid homeostasis in aged mice. Hepatology. doi: 10.1002/hep.29199.

3. Desai MS, Mathur B, Eblimit Z, Vasquez H, Taegtmeyer H, Karpen SJ, Penny DJ, Moore DD, Anakk S. (2017) Bile acid excess induces cardiomyopathy and metabolic dysfunctions in the heart. Hepatology. 65(1):189-201. doi: 10.1002/hep.28890

4. Bhate A, Parker DJ, Bebee TW, Ahn J, Arif W, Rashan EH, Chorghade S, Chau A, Lee JH, Anakk S, Carstens RP, Xiao X, Kalsotra A. (2015) ESRP2 controls an adult splicing programme in hepatocytes to support postnatal liver maturation. Nature Commun. 6:8768. doi: 10.1038/ncomms9768.

5. Chow EC, Magomedova L, Quach HP, Patel RH, Durk MR, Fan J, Maeng HJ, Irondi K, Anakk S, Moore DD, Cummins CL, Pang KS. (2014) Vitamin D Receptor Activation Down-regulates Small Heterodimer Partner and Increases CYP7A1 to Lower Cholesterol. Gastroenterology 146(4):1048-59. doi: 10.1053/j.gastro.2013.12.027.

6. Kerr TA, Matsumoto Y, Matsumoto H, Xie Y, Hirschberger LL, Stipanuk MH, Anakk S, Moore DD, Watanabe M, Kennedy S, Davidson NO. (2014) Cysteine sulfinic acid decarboxylase regulation: A role for farnesoid X receptor and small heterodimer partner in murine hepatic taurine metabolism. Hepatology Research 44(10):E218-28. doi: 10.1111/hepr.12230. Epub 2013 Oct 18.

7. Anakk S*, Bhosale M, Schmidt VA, Johnson RL, Finegold MJ, Moore DD*. (2013) Bile Acids Activate YAP to Promote Liver Carcinogenesis. Cell Reports 5(4):1060-9. *corresponding author

8. Jiang Y, Iakova P, Jin J, Sullivan E, Sharin V, Hong IH, Anakk S, Mayor A, Darlington G, Finegold M, Moore D, Timchenko NA. (2013) FXR inhibits gankyrin in mouse livers and prevents development of liver cancer. Hepatology 57(3):1098-106. doi: 10.1002/hep.26146.

9. Anakk S, Watanabe M, Ochsner SA, McKenna NJ, Finegold MJ and Moore DD. (2011) Combined deletion of FXR and SHP results in juvenile onset cholestasis and induction of Cyp17A1. Journal of Clinical Investigation 121(1):86-95.

10. Park YJ, Kim SC, Kim J, Anakk S, Lee JM, Tseng HT, Yechoor V, Park J, Choi JS, Jang HC, Lee KU, Novak CM, Moore DD, Lee YK. (2011) Dissociation of diabetes and obesity in mice lacking orphan nuclear receptor small heterodimer partner. Journal of Lipid Research 52(12):2234-44.

11. Dwivedi SK, Singh N, Kumari R, Mishra JS, Tripathi S, Banerjee P, Shah P, Kukshal V, Tyagi AM, Gaikwad AN, Chaturvedi RK, Mishra DP, Trivedi AK, Sanyal S, Chattopadhyay N, Ramachandran R, Siddiqi MI, Bandyopadhyay A, Arora A, Lundåsen T, Anakk S, Moore DD, Sanyal S. (2011) Bile acid receptor agonist GW4064 regulates PPARγ coactivator-1α expression through estrogen receptor-related receptor α. Molecular Endocrinology 25(6):922-32.

12. Anakk S, Huang W, Staudinger JL, Tan K, Cole TJ, Moore DD and Strobel HW. (2007) Gender dictates the nuclear receptor-mediated regulation of CYP3A44. Drug Metabolism and Disposition 35(1):36-42.

13. Anakk S, Kalsotra A, Kikuta Y, Huang W, Zhang J, Staudinger JL, Moore DD, and Strobel HW. (2004) CAR/PXR provide directives for Cyp3a41 gene regulation differently from Cyp3a11. The Pharmacogenomics Journal 4(2):91-101.

14. Anakk S, Kalsotra A, Shen Q, Vu MT, Staudinger JL, Davies PJ and Strobel HW. (2003) Genomic characterization and regulation of CYP3a13: role of xenobiotics and nuclear receptors. The FASEB Journal 17(12):1736-8.

15. Anakk S, Ku C, Davies PJ and Strobel HW. (2003) Insights into gender bias: Role of CYP3A9. Journal of Pharmacology & Experimental Therapeutics 305(2):703-9.

Book Chapters

1. Anakk S (2008). HIV case #5 in Casefiles: Biochemistry. E Toy, W Seifert Jr., HW Strobel and K Harms (eds), LANGE SERIES 2nd edition by Mcgraw-Hill UK, 41-49.

2. Anakk S (2008). Beta Thalassaemia case #12 in Casefiles: Biochemistry. E Toy, W Seifert Jr., HW Strobel and K Harms (eds), LANGE SERIES 2nd edition by Mcgraw-Hill UK,103-110.

Complete Publications List