Fatty liver disorders affect more than 20% of Americans;however, there are no effective treatment options. The enzymes acetyl-CoA carboxylase (ACC) 1 and ACC2 promote fat synthesis in the liver;therefore, they are attractive drug targets for fatty liver disease and related disorders. To determine how the loss of ACC activity in the liver affects hepatic and whole body metabolism, we generated liver-specific ACC1 and ACC2 double knockout mice (LDKO). We find that these mice are protected from diet-induced glucose intolerance, but accumulate an unexpected increase in liver fat. Our preliminary data suggest that when ACC enzymes are inhibited their substrate acetyl-CoA is used for protein acetylation. In this study we will test the consequences of long-term ACC inhibition on fatty liver disease pathologies and we will determine whether maintaining some residual ACC activity at ACC1 or ACC2 may uncouple the positive effects on glucose tolerance from the increased fat accumulation by preventing protein hyper-acetylation. This work will advance our understanding of the molecular regulation of liver metabolism by ACC enzymes. In addition, this study will guide future pharmacology in the area of developing liver-targeted isotype-sparing ACC inhibitors for the treatment fatty liver disease and related metabolic disorders.

Public Health Relevance

Liver diseases are progressive metabolic disorders that can lead to type II diabetes, hepatocellular cancer, and cardiovascular disease. The current project investigates a role for the enzymes acetyl-CoA carboxylase (ACC) 1 and ACC2 in the regulation of hepatic fat or glucose metabolism via a novel mechanism involving protein acetylation. This study will advance our understanding of the molecular regulation of liver metabolism.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK101803-01A1
Application #
8818526
Study Section
Hepatobiliary Pathophysiology Study Section (HBPP)
Program Officer
Doo, Edward
Project Start
2014-09-27
Project End
2018-08-31
Budget Start
2014-09-27
Budget End
2015-08-31
Support Year
1
Fiscal Year
2014
Total Cost
$355,500
Indirect Cost
$130,500
Name
University of Virginia
Department
Pharmacology
Type
Schools of Medicine
DUNS #
065391526
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
Nelson, Marin E; Lahiri, Sujoy; Chow, Jenny D Y et al. (2017) Inhibition of hepatic lipogenesis enhances liver tumorigenesis by increasing antioxidant defence and promoting cell survival. Nat Commun 8:14689
Gordon, Hannah M; Majithia, Neil; MacDonald, Patrick E et al. (2017) STEAP4 expression in human islets is associated with differences in body mass index, sex, HbA1c, and inflammation. Endocrine 56:528-537
Taddeo, Evan P; Hargett, Stefan R; Lahiri, Sujoy et al. (2017) Lysophosphatidic acid counteracts glucagon-induced hepatocyte glucose production via STAT3. Sci Rep 7:127
Brandon, Amanda E; Stuart, Ella; Leslie, Simon J et al. (2016) Minimal impact of age and housing temperature on the metabolic phenotype of Acc2-/- mice. J Endocrinol 228:127-34
Narayanan, Sowmya; Nieh, Albert H; Kenwood, Brandon M et al. (2016) Distinct Roles for Intracellular and Extracellular Lipids in Hepatitis C Virus Infection. PLoS One 11:e0156996
Byrne, Frances L; Hoehn, Kyle L (2016) Subclassification of fatty liver by its pathogenesis: cIEFing is believing. J Pathol 239:3-5
Healy, Marin E; Lahiri, Sujoy; Hargett, Stefan R et al. (2016) Dietary sugar intake increases liver tumor incidence in female mice. Sci Rep 6:22292
Laker, Rhianna C; Taddeo, Evan P; Akhtar, Yasir N et al. (2016) The Mitochondrial Permeability Transition Pore Regulator Cyclophilin D Exhibits Tissue-Specific Control of Metabolic Homeostasis. PLoS One 11:e0167910
Biwer, Lauren A; Taddeo, Evan P; Kenwood, Brandon M et al. (2016) Two functionally distinct pools of eNOS in endothelium are facilitated by myoendothelial junction lipid composition. Biochim Biophys Acta 1861:671-9
Healy, Marin E; Chow, Jenny D Y; Byrne, Frances L et al. (2015) Dietary effects on liver tumor burden in mice treated with the hepatocellular carcinogen diethylnitrosamine. J Hepatol 62:599-606

Showing the most recent 10 out of 15 publications