Obesity is associated with increased incidence of a number of chronic and progressive diseases including diabetes, cardiovascular disease, cancer, and nonalcoholic steatohepatitis (NASH). With the epidemic of obesity in the U.S., the occurrence of NASH has risen exuberantly, becoming the most common cause of liver disease. The root cause of NASH is likely the chronic oversupply of fatty acids leading to lipid accumulation within the cytosol of hepatocytes (hepatic steatosis). Although hepatic steatosis is extremely prevalent, only a subset of afflicted individuals exhibit NASH, severe liver damage, or progress to cirrhosis. The progressive mechanisms are not entirely clear, but likely involve an inflammatory state including augmented production of reactive oxygen species (ROS) and pro-inflammatory cytokines. This second hit is believed to be required to drive the transition from simple steatosis to steatohepatitis. This application is designed to examine the effects of novel compounds (MSDC-0602 and -0160) on a mouse model of NASH and to tease apart the mechanisms of their action. We have shown in studies conducted in obese rodent models that MSDC compounds improve hepatic and skeletal muscle insulin resistance. Phase 2 clinical trials for these drugs have demonstrated efficacy as a glucose lowering and insulin-sensitizing agents. However, little is known regarding the efficacy of these, and related compounds, for treatment of NASH. We propose to evaluate the effects of MSDC-0602 and -0160 on the development of NASH in rodent models (Aim 1), conduct proof of concept studies to define the mechanistic target and mechanisms of action of MSDC drugs (Aim 2), and to identify novel small molecules with similar modes of action (Aim 3). Successful completion of these studies will provide proof of concept efficacy data to drive clinical trials in human subjects with NASH. Moreover, understanding the mechanism of action of these compounds fully could lead to the identification of new compounds with similar pharmacology and effectiveness as new drug leads to treat this and other chronic metabolic and inflammatory conditions.

Public Health Relevance

We have developed new drugs that we believe will be useful for treating nonalcoholic steatohepatitis (NASH), which is a common disease in the U.S. caused by having too much fat in the liver. The goal of this project is to test this idea in mice and to determine the mechanisms by how these drugs work. Successful completion of these studies could pave the way to clinical development of a pharmaceutical therapy for treatment of NASH.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
3R01DK104735-05S1
Application #
9955982
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Doo, Edward
Project Start
2015-04-01
Project End
2021-03-31
Budget Start
2019-04-01
Budget End
2021-03-31
Support Year
5
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Washington University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Finck, Brian N (2018) Targeting Metabolism, Insulin Resistance, and Diabetes to Treat Nonalcoholic Steatohepatitis. Diabetes 67:2485-2493
Chen, Yana; McCommis, Kyle S; Ferguson, Daniel et al. (2018) Inhibition of the Mitochondrial Pyruvate Carrier by Tolylfluanid. Endocrinology 159:609-621
Liss, Kim H H; McCommis, Kyle S; Chambers, Kari T et al. (2018) The impact of diet-induced hepatic steatosis in a murine model of hepatic ischemia/reperfusion injury. Liver Transpl 24:908-921
Hall, Angela M; Finck, Brian N (2017) ChREBP refines the hepatic response to fructose to protect the liver from injury. J Clin Invest 127:2533-2535
Vigueira, Patrick A; McCommis, Kyle S; Hodges, Wesley T et al. (2017) The beneficial metabolic effects of insulin sensitizers are not attenuated by mitochondrial pyruvate carrier 2 hypomorphism. Exp Physiol 102:985-999
McCommis, Kyle S; Hodges, Wesley T; Brunt, Elizabeth M et al. (2017) Targeting the mitochondrial pyruvate carrier attenuates fibrosis in a mouse model of nonalcoholic steatohepatitis. Hepatology 65:1543-1556
Liss, Kim H H; Finck, Brian N (2017) PPARs and nonalcoholic fatty liver disease. Biochimie 136:65-74
McCommis, Kyle S; Hodges, Wesley T; Bricker, Daniel K et al. (2016) An ancestral role for the mitochondrial pyruvate carrier in glucose-stimulated insulin secretion. Mol Metab 5:602-14
Lam, Wing Y; Becker, Amy M; Kennerly, Krista M et al. (2016) Mitochondrial Pyruvate Import Promotes Long-Term Survival of Antibody-Secreting Plasma Cells. Immunity 45:60-73
McCommis, Kyle S; Finck, Brian N (2015) Mitochondrial pyruvate transport: a historical perspective and future research directions. Biochem J 466:443-54

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