Abstract

Both alcoholic and non-alcoholic fatty liver diseases (AFLD and NAFLD, respectively) cause serious health problems in the US. AFLD occurs in nearly all excessive alcohol drinkers and NAFLD afflicts approximately one-third of adult population. Worse yet, there is no effective treatment for either AFLD or NAFLD at this time. In this proposed research, we plan to investigate molecular mechanisms of Sestrin3 (Sesn3) in the regulation of hepatic lipid metabolism. There are two specific aims in this project.
Aim# 1 is to determine the protective mechanism of Sesn3 against AFLD and NAFLD through the Atg14-regulated autophagy pathway.
Aim #2 is to examine the role of Sesn3-mTORC2 pathway in the pathogenesis of AFLD and NAFLD. It is anticipated that the findings from this proposed research should provide valuable information for therapeutic development to treat AFLD and NAFLD.

Public Health Relevance

/PUBLIC HEALTH RELEVANCE STATEMENT With the increasing prevalence of obesity and excessive alcohol use, alcoholic and non-alcoholic fatty liver disease (AFLD and NAFLD) have become the major health problems in the United States. We have recently identified that Sestrin3 is the key regulator in the pathogenesis of both AFLD and NAFLD. We propose to investigate the mechanism and regulation of Sestrin3 in AFLD and NAFLD; if successful, the results should provide much needed information for the development of novel therapeutics for AFLD and NAFLD by targeting the Sestrin3 pathway.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK107682-04
Application #
9734896
Study Section
Hepatobiliary Pathophysiology Study Section (HBPP)
Program Officer
Doo, Edward
Project Start
2016-07-01
Project End
2020-06-30
Budget Start
2019-07-01
Budget End
2020-06-30
Support Year
4
Fiscal Year
2019
Total Cost
Indirect Cost

  Institution

Name
Indiana University-Purdue University at Indianapolis
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
603007902
City
Indianapolis
State
IN
Country
United States
Zip Code
46202

  Publications

Chang, Binxia; Hao, Shuli; Zhang, Longyu et al. (2018) Association Between Aldehyde Dehydrogenase 2 Glu504Lys Polymorphism and Alcoholic Liver Disease. Am J Med Sci 356:10-14
Liangpunsakul, Suthat; Beaudoin, James J; Shah, Vijay H et al. (2018) Interaction between the patatin-like phospholipase domain-containing protein 3 genotype and coffee drinking and the risk for acute alcoholic hepatitis. Hepatol Commun 2:29-34
Jinjuvadia, Raxitkumar; Jinjuvadia, Chetna; Puangsricharoen, Pimpitcha et al. (2018) Concomitant Psychiatric and Nonalcohol-Related Substance Use Disorders Among Hospitalized Patients with Alcoholic Liver Disease in the United States. Alcohol Clin Exp Res 42:397-402
Walline, Crystal C; Blum, Janice S; Linton, Tobyn et al. (2018) Early activation of peripheral monocytes with hallmarks of M1 and M2 monocytic cells in excessive alcohol drinkers: a pilot study. J Investig Med 66:1-4
Dong, X Charlie (2018) SCP4: A Small Nuclear Phosphatase Having a Big Effect on FoxOs in Gluconeogenesis. Diabetes 67:23-25
Tao, Rongya; Wang, Caixia; Stöhr, Oliver et al. (2018) Inactivating hepatic follistatin alleviates hyperglycemia. Nat Med 24:1058-1069
Hollister, Kristin; Kusumanchi, Praveen; Ross, Ruth Ann et al. (2018) Levels of circulating follicular helper T cells, T helper 1 cells, and the prognostic significance of soluble form of CD40 ligand on survival in patients with alcoholic cirrhosis. Liver Res 2:52-59
Pan, Xiaoyan; Zhang, Yang; Kim, Hyeong-Geug et al. (2017) FOXO transcription factors protect against the diet-induced fatty liver disease. Sci Rep 7:44597
Shen, Huafeng; Peng, Jennifer L; Tayarachakul, Sucharat et al. (2017) Association between serum cotinine level and prevalence of non-alcoholic fatty liver disease: a cross-sectional study from the Third National Health and Nutrition Examination Survey. J Investig Med 65:43-48
Zhao, Yulan; Wu, Jianguo; Liangpunsakul, Suthat et al. (2017) Long Non-coding RNA in Liver Metabolism and Disease: Current Status. Liver Res 1:163-167

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