The DOI matches its Crossref record; 53 of the 53 references it cites were found in a registry or an index.
GS-0976 (Firsocostat): an investigational liver-directed acetyl-CoA carboxylase (ACC) inhibitor for the treatment of non-alcoholic steatohepatitis (NASH)
Open accessAbstract
Introduction: De novo lipogenesis (DNL) plays a major role in fatty acid metabolism and contributes significantly to triglyceride accumulation within the hepatocytes in patients with nonalcoholic steatohepatitis (NASH). Acetyl-CoA carboxylase (ACC) converts acetyl-CoA to malonyl CoA and is a rate-controlling step in DNL. Furthermore, malonyl-CoA is an important regulator of hepatic mitochondrial fat oxidation through its ability to inhibit carnitine palmitoyltransferase I. Therefore, inhibiting ACC pharmacologically represents an attractive approach to treating NASH.Areas covered: This article summarizes preclinical and clinical data on the efficacy and safety of the liver-targeted ACC inhibitor GS-0976 (Firsocostat) for the treatment of NASH. In a phase 2 trial that included 126 patients with NASH and fibrosis, GS-0976 20 mg daily for 12 weeks showed significant relative reduction in liver fat by 29%; however, treatment was associated with an increase in plasma triglycerides with 16 patients having levels >500 mg/dL.Expert opinion: Preclinical and preliminary clinical data support the development of GS-0976 as treatment for NASH. ACC-induced hypertriglyceridemia can be mitigated by fish oil or fibrates, but the long-term cardiovascular effects require further investigations.
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“Farnesoid X receptor (FXR) is a bile acid receptor that inhibits lipogenesis and bile acid synthesis while acetyl-CoA carboxylase (ACC) is a catalyst for the irreversible carboxylation of acetyl coenzyme A to produce malonyl-CoA, the rate limiting step for de novo lipogenesis in the liver.53,54”
From Management of type 2 diabetes, obesity, or nonalcoholic steatohepatitis with high‐dose GLP‐1 receptor agonists and GLP‐1 receptor‐based co‐agonists (2024) · cites this paper as [53]
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“ACC also impairs β-oxidation of fatty acids.53”
From Management of type 2 diabetes, obesity, or nonalcoholic steatohepatitis with high‐dose GLP‐1 receptor agonists and GLP‐1 receptor‐based co‐agonists (2024) · cites this paper as [53]
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Self-citationAngulo, P., Kleiner, D. E., Dam-Larsen, S., Adams, L. A., Bjornsson, E. S., Charatcharoenwitthaya, P., Mills, P. R., Keach, J. C., Lafferty, H. D., Stahler, A., et al. (2015) · Gastroenterology · doi:10.1053/j.gastro.2015.04.043 · Cited by 2,987
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“patients without NAFLD with similar rates of adipose flux of fatty acids (FAs) [15].”
Background
Research works printed but not linked: 2
- Younossi Z, 2019, Hepatology, 70
- Bates J, 2017, Hepatology, 66, Abstract425
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Metadata
- Authors
- Alkhouri, N., Lawitz, E., Noureddin, M., DeFronzo, R., & Shulman, G. I.
- Affiliations
- The University of Texas at San Antonio Health Science Center (US)
- Cedars-Sinai Medical Center (US)
- Yale University (US)
- Corresponding author
- Alkhouri, Naim
- Venue
- Expert Opinion on Investigational Drugs
- Publisher
- Informa UK Limited
- Published
- 2019-09-19
- Volume
- 29
- Issue
- 2
- Pages
- 135-141
- ISSN
- 1354-3784 (ISSN-L)
- 1744-7658
- PMC
- PMC7063378
- OpenAlex
- W2973125925
- Cited by
- 162
- References
- 53
- Citations by year
- 2026: 16 · 2025: 23 · 2024: 29 · 2023: 24 · 2022: 24 · 2021: 26 · 2020: 19 · 2019: 1
- FWCI
- 14.08
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Expert Opinion on Investigational Drugs (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (UL1TR001863)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK119968, R01DK114793, R01DK116774, R01DK113984, P30DK034989, P30DK045735)
- National Center for Advancing Translational Sciences
- Topics
- Health Sciences › Medicine › Hepatology › Liver Disease Diagnosis and Treatment
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
- Keywords
- acetyl-CoA carboxylase inhibitors, nonalcoholic steatohepatitis, de novo lipogenesis, hepatic lipid accumulation, hypertriglyceridemia, liver fibrosis, fish oil, fibrates, cardiovascular safety, malonyl-CoA
- MeSH terms
- Acetyl-CoA Carboxylase, Animals, Enzyme Inhibitors, Fatty Acids, Humans, Oxazoles, Pyrimidines, Triglycerides, Drugs, Investigational, Lipogenesis, Isobutyrates, Non-alcoholic Fatty Liver Disease
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