Obesity is associated with an increased risk of a number of chronic and progressive diseases and obesity-related metabolic diseases constitute a significant public health burden. It has long been known that obesity is linked to increased risk of type 2 diabetes precipitated by resistance to the effects of insulin. Over the past few years, there is also increased awareness that obesity is strongly associated with accumulation of lipid in the liver parenchyma (nonalcoholic fatty liver disease (NAFLD)). The term, NAFLD, encompasses both hepatic steatosis (the accumulation of neutral lipid within the cytosol of hepatocytes) and the more severe nonalcoholic steatohepatitis (NASH) (hepatic inflammation and fibrosis associated with steatotic lesions). A significant proportion of NAFLD and NASH patients will progress to cirrhosis and liver failure and are at increased risk for developing hepatocellular carcinoma. NASH is currently a disease without an approved treatment and constitutes a significant unmet medical need. Current therapeutic development is focused on drugs that either target fibrosis or aim to reduce hepatic lipid content. In clinical trials to date, insulin-sensitizing thiazolidinediones (TZDs) known to be ligands for the PPAR? nuclear receptor have shown some of the strongest effects on NASH of any experimental drugs. In the previous period of support provided by this grant, we tested the novel hypothesis that TZDs also engage and inhibit the mitochondrial pyruvate carrier (MPC). Indeed, we found that a next generation TZD (MSDC-0602) that engaged the MPC, but had markedly attenuated ability to activate PPAR?, reduced stellate cell activation and other NASH endpoints in a mouse model. Moreover, mice with hepatocyte-specific MPC deletion were protected from developing insulin resistance, diabetes, and NASH. On the strength of this and other experimental data, MSDC-0602 was advanced to a one-year, Phase 2b clinical trial (EMMINENCE: NCT02784444). During the previous period of support, we also identified a number of candidate compounds that act as MPC inhibitors and have preliminary data that these inhibitors also improve insulin sensitivity. Although there is now good evidence supporting the key premise that targeting the MPC is a viable therapeutic approach for treating NASH, many questions remain regarding the molecular mechanisms by which MPC inhibition leads to beneficial metabolic and anti-fibrotic effects. In addition, previous work has primarily focused on the MPC in hepatocytes; the effects on stellate cells, which are critical to the development of NASH, have not been explored. This application has 3 overarching goals: [1] To test the hypothesis that novel MPC inhibitors will improve insulin sensitivity and NASH endpoints in mice. [2] To tease apart the molecular mechanisms of action of MPC modulators on insulin resistance and NASH endpoints. [3] To test the hypothesis that targeting the MPC in stellate cells contributes to the beneficial effects of MPC inhibitors. The overarching premise of this application is that targeting the MPC in hepatocytes and stellate cells will be useful for treating insulin resistance and NASH. These studies will define molecular mechanisms and provide proof-of-concept evidence supporting future clinical trials to test the efficacy of these drugs in patients with diabetes, NASH, and other obesity-related cardiometabolic diseases.

Public Health Relevance

We have developed new drugs that we believe will be useful for treating insulin resistance and 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 #
2R01DK104735-06A1
Application #
10145157
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Doo, Edward
Project Start
2015-04-01
Project End
2024-12-31
Budget Start
2021-01-27
Budget End
2021-12-31
Support Year
6
Fiscal Year
2021
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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