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Cited by 217Liver Disease Diagnosis and TreatmentDrug-Induced Hepatotoxicity and ProtectionLiver physiology and pathology

Acetyl-CoA Carboxylase Inhibitor GS-0976 for 12 Weeks Reduces Hepatic De Novo Lipogenesis and Steatosis in Patients With Nonalcoholic Steatohepatitis

Lawitz, Eric J., Coste, Angie, Poordad, Fred, Alkhouri, Naim, Loo, Nicole, McColgan, Bryan J., Tarrant, Jacqueline M., Nguyen, Tuan +13 more·2018·Clinical Gastroenterology and Hepatology
DOI 10.1016/j.cgh.2018.04.042
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Abstract

Background & aims Increased de novo lipogenesis (DNL) contributes to the pathogenesis of nonalcoholic steatohepatitis (NASH). Acetyl-CoA carboxylase catalyzes the rate-limiting step in DNL. We evaluated the safety and efficacy of GS-0976, a small molecule inhibitor of acetyl-CoA carboxylase, in patients with NASH. Methods In an open-label prospective study, patients with NASH (n = 10) received GS-0976 20 mg orally once daily for 12 weeks. NASH was diagnosed based on a proton density fat fraction estimated by magnetic resonance imaging (MRI-PDFF) ≥10% and liver stiffness by magnetic resonance elastography (MRE) ≥2.88 kPa. The contribution from hepatic DNL to plasma palmitate was measured by 14 days of heavy water labeling before and at the end of treatment. We performed the same labelling protocol in an analysis of healthy volunteers who were not given DNL (controls, n = 10). MRI-PDFF and MRE at baseline, and at weeks 4 and 12 of GS-0976 administration, were measured. We analyzed markers of liver injury and serum markers of fibrosis. Results The contribution of hepatic DNL to plasma palmitate was significantly greater in patients with NASH compared with controls (43% vs 18%) (P = .003). After 12 weeks administration of GS-0976, the median hepatic DNL was reduced 22% from baseline in patients with NASH (P = .004). Compared with baseline, reductions in MRI-PDFF at week 12 (15.7% vs 9.1% at baseline; P = .006), liver stiffness by MRE (3.4 kPa vs 3.1 kPa at baseline; P = .049), TIMP metallopeptidase inhibitor 1 (275 ng/mL vs 244 ng/mL at baseline; P = .049), and serum level of alanine aminotransferase (101 U/L vs 57 U/L at baseline; P = .23) were consistent with decreased hepatic lipid content and liver injury. At week 12, 7 patients (70%) had a ≥30% decrease in MRI-PDFF. Conclusion In an open-label study, patients with NASH given GS-0976 for 12 weeks had reduced hepatic DNL, steatosis, and markers of liver injury. ClinicalTrials.gov no: NCT02856555.

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  • In obesity and insulin resistance, not only influx of NEFA to liver increases considerably, but also DNL shows an up to five-fold rise.

    “In obesity and insulin resistance, not only the influx of NEFA to the liver increases considerably, but also DNL shows an up to five-fold rise [220,221]”

    From Obesity and MASLD: Is weight loss the (only) key to treat metabolic liver disease? (2024) · cites this paper as [221]

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Authors
Lawitz, E. J., Coste, A., Poordad, F., Alkhouri, N., Loo, N., McColgan, B. J., Tarrant, J. M., Nguyen, T., Han, L., Chung, C., Ray, A. S., McHutchison, J. G., Subramanian, G. M., Myers, R. P., Middleton, M. S., Sirlin, C., Loomba, R., Nyangau, E., Fitch, M., Li, K., & Hellerstein, M.
Affiliations
  • The University of Texas at San Antonio Health Science Center (US)
  • Gilead Sciences (United States) (US)
  • University of California San Diego (US)
  • University of California, Berkeley (US)
Corresponding author
Lawitz, Eric J.
ORCID
Venue
Clinical Gastroenterology and Hepatology
Publisher
Elsevier BV
Published
2018-12
Volume
16
Issue
12
Pages
1983-1991.e3
ISSN
1542-3565 (ISSN-L)
DOI
10.1016/j.cgh.2018.04.042
OpenAlex
W2799863868
Cited by
217
References
3
Citations by year
2026: 9 · 2025: 20 · 2024: 28 · 2023: 22 · 2022: 29 · 2021: 37 · 2020: 42 · 2019: 18 · 2018: 12
FWCI
21.37
Type
journal article
Language
en
Open access
closed
Licence
Locations
  • Clinical Gastroenterology and Hepatology (publishedVersion)
  • PubMed (publishedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
Topics
  • Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
  • Health Sciences › Medicine › Hepatology › Liver physiology and pathology
Keywords
nonalcoholic steatohepatitis, acetyl-CoA carboxylase inhibitors, de novo lipogenesis, hepatic steatosis, liver fibrosis, liver stiffness, MRI-PDFF, heavy water labeling, TIMP-1, alanine aminotransferase, drug safety and efficacy
MeSH terms
Acetyl-CoA Carboxylase, Administration, Oral, Adolescent, Adult, Aged, Enzyme Inhibitors, Female, Humans, Liver, Magnetic Resonance Imaging, Male, Middle Aged, Oxazoles, Prospective Studies, Pyrimidines, Treatment Outcome, Lipogenesis, Elasticity Imaging Techniques, Young Adult, Isobutyrates, Non-alcoholic Fatty Liver Disease

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