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Hepatocyte-specific suppression of ANGPTL4 improves obesity-associated diabetes and mitigates atherosclerosis in mice
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Abstract
Hepatic uptake and biosynthesis of fatty acids (FA), as well as the partitioning of FA into oxidative, storage, and secretory pathways are tightly regulated processes. Dysregulation of one or more of these processes can promote excess hepatic lipid accumulation, ultimately leading to systemic metabolic dysfunction. Angiopoietin-like-4 (ANGPTL4) is a secretory protein that inhibits lipoprotein lipase (LPL) and modulates triacylglycerol (TAG) homeostasis. To understand the role of ANGPTL4 in liver lipid metabolism under normal and high-fat fed conditions, we generated hepatocyte specific Angptl4 mutant mice (Hmut). Using metabolic turnover studies, we demonstrate that hepatic Angptl4 deficiency facilitates catabolism of TAG-rich lipoprotein (TRL) remnants in the liver via increased hepatic lipase (HL) activity, which results in a significant reduction in circulating TAG and cholesterol levels. Consequently, depletion of hepatocyte Angptl4 protects against diet-induce obesity, glucose intolerance, liver steatosis, and atherogenesis. Mechanistically, we demonstrate that loss of Angptl4 in hepatocytes promotes FA uptake which results in increased FA oxidation, ROS production, and AMPK activation. Finally, we demonstrate the utility of a targeted pharmacologic therapy that specifically inhibits Angptl4 gene expression in the liver and protects against diet-induced obesity, dyslipidemia, glucose intolerance, and liver damage, which likely occurs via increased HL activity. Notably, this novel inhibition strategy does not cause any of the deleterious effects previously observed with neutralizing antibodies.
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“hepatocyte-specific deletion of ANGPTL4 attenuated obesity, liver steatosis, and atherosclerosis in high-fat-diet mice [32].”
From Identifying novel drug targets for calcific aortic valve disease through Mendelian randomization (2025) · cites this paper as [32]
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Metadata
- Authors
- Singh, A. K., Chaube, B., Zhang, X., Sun, J., Citrin, K. M., Canfrán-Duque, A., Aryal, B., Rotllan, N., Varela, L., Lee, R. G., Horvath, T. L., Price, N. L., Suárez, Y., & Fernández-Hernando, C.
- Affiliations
- Yale University (US)
- Ionis Pharmaceuticals (United States) (US)
- Corresponding author
- Suárez, Yajaira
- ORCID
- Venue
- Journal of Clinical Investigation
- Published
- 2021-09-01
- Volume
- 131
- Issue
- 17
- ISSN
- 0021-9738 (ISSN-L)
- 1558-8238
- PMC
- PMC8409581
- OpenAlex
- W3182800692
- Cited by
- 115
- References
- 78
- Citations by year
- 2026: 12 · 2025: 29 · 2024: 28 · 2023: 16 · 2022: 17 · 2021: 12
- FWCI
- 12.40
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Heart, Lung, and Blood Institute (R35HL135820)
- National Institute of Diabetes and Digestive and Kidney Diseases (5F32DK10348902)
- American Heart Association (16EIA27550005, 20TPA35490202, 17SDG33110002, 20TPA35490416)
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Lipid metabolism and biosynthesis
- Health Sciences › Medicine › Hepatology › Liver Disease Diagnosis and Treatment
- Keywords
- ANGPTL4, hepatocyte-specific knockout, hepatic lipid metabolism, hepatic lipase, lipoprotein lipase, diet-induced obesity, impaired glucose tolerance, hepatic steatosis, atherosclerosis, fatty acid oxidation, AMPK activation, reactive oxygen species, dyslipidemia
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