Acetyl CoA carboxylase inhibition reduces hepatic steatosis but elevates plasma triglycerides in mice and humans: a bedside to bench investigation
Open accessAbstract
Inhibiting lipogenesis prevents hepatic steatosis in rodents with insulin resistance. To determine if reducing lipogenesis functions similarly in humans, we developed MK-4074, a liver-specific inhibitor of acetyl-CoA carboxylase (ACC1) and (ACC2), enzymes that produce malonyl-CoA for fatty acid synthesis. MK-4074 administered to subjects with hepatic steatosis for 1 month lowered lipogenesis, increased ketones, and reduced liver triglycerides by 36%. Unexpectedly, MK-4074 increased plasma triglycerides by 200%. To further investigate, mice that lack ACC1 and ACC2 in hepatocytes (ACC dLKO) were generated. Deletion of ACCs decreased polyunsaturated fatty acid (PUFA) concentrations in liver due to reduced malonyl-CoA, which is required for elongation of essential fatty acids. PUFA deficiency induced SREBP-1c, which increased GPAT1 expression and VLDL secretion. PUFA supplementation or siRNA-mediated knockdown of GPAT1 normalized plasma triglycerides. Thus, inhibiting lipogenesis in humans reduced hepatic steatosis, but inhibiting ACC resulted in hypertriglyceridemia due to activation of SREBP-1c and increased VLDL secretion.
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Peptides derived from L. platensis inhibit ACC activity, thereby reducing fatty acid synthesis and limiting lipid accumulation in hepatic and adipose tissues.
“Peptides derived from L. platensis inhibit ACC activity, thereby reducing fatty acid synthesis and limiting lipid accumulation in hepatic and adipose tissues [151–153].”
From Navigating the potential of algal peptides: health effects, market applications, and scientific challenges (2026) · cites this paper as [151]
The Discussion reports that inhibiting ACC reduces de novo lipogenesis and liver triglycerides, supporting the hepatic mechanism. But this paper studies the liver-targeted inhibitor MK-4074 and ACC deletion, not peptides derived from L. platensis; it also does not establish reduced lipid accumulation in adipose tissue. (LLM, conf=0.89)
Experimental — accuracy not yet measuredInhibition of acetyl-CoA carboxylase decreases DNL and IHTG content in mice fed a high-fat/high-sucrose diet and in individuals with MASLD.
“Furthermore, the inhibition of acetyl-CoA carboxylase, the primary regulator of fatty acid synthesis, decreases DNL and IHTG content in mice fed a high-fat/high-sucrose diet and in individuals with MASLD.30”
From Lipid metabolism in MASLD and MASH: From mechanism to the clinic (2024) · cites this paper as [30]
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- Authors
- Kim, C.-W., Addy, C., Kusunoki, J., Anderson, N. N., Deja, S., Fu, X., Burgess, S. C., Li, C., Ruddy, M., Chakravarthy, M., Previs, S., Milstein, S., Fitzgerald, K., Kelley, D. E., & Horton, J. D.
- Affiliations
- The University of Texas Southwestern Medical Center (US)
- Alnylam Pharmaceuticals (United States) (US)
- Corresponding author
- Horton, Jay D.
- ORCID
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2017-08
- Volume
- 26
- Issue
- 2
- Pages
- 394-406.e6
- ISSN
- 1550-4131 (ISSN-L)
- PMC
- PMC5603267
- OpenAlex
- W2740884150
- Cited by
- 419
- References
- 61
- Citations by year
- 2026: 33 · 2025: 32 · 2024: 59 · 2023: 60 · 2022: 50 · 2021: 61 · 2020: 56 · 2019: 42 · 2018: 24 · 2017: 1
- FWCI
- 26.34
- Type
- journal article
- Language
- en
- Update notices
- erratum (2017-09-05)
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (HL-20948)
- Leducq Foundation
- Topics
- Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Lipid metabolism and biosynthesis
- Keywords
- acetyl-CoA carboxylase inhibition, hepatic steatosis, lipogenesis, plasma triglycerides, hypertriglyceridemia, malonyl-CoA, ketone bodies, polyunsaturated fatty acids, SREBP-1c, GPAT1, VLDL secretion, insulin resistance, liver-specific gene deletion
- MeSH terms
- Acetyl-CoA Carboxylase, Animals, Enzyme Inhibitors, Fatty Liver, Humans, Lipoproteins, VLDL, Triglycerides, Mice, Knockout, Hepatocytes, Mice, Sterol Regulatory Element Binding Protein 1
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