ArticleThe Journal of clinical investigation2021
Hepatocyte-specific suppression of ANGPTL4 improves obesity-associated diabetes and mitigates atherosclerosis in mice.
Article in The Journal of clinical investigation, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 62 papers.
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Who cites it
62 citing papers in PubMed, 108 citations in OpenAlex.
- Key Hepatokines Linking MASLD and Type 2 Diabetes: From Pathophysiological Mechanisms to Therapeutic Modulation.International journal of molecular sciences · 2026Review
- Amifostine alleviates ionizing radiation-induced small intestinal motility dysfunction in mice by remodeling the structure of the enteric nervous system.Histochemistry and cell biology · 2026Article
- HlncRNA-1 integrates the hepatic circadian clock with lipid metabolism by targeting Hdlbp.Communications biology · 2026Article
- Impaired glycosylation promotes rapid transition to hepatocellular carcinoma in model of diet-induced steatotic liver disease.The Journal of clinical investigation · 2026Article
- Role of L-Arginine in the Gut-Liver Axis of Female Mice: Mediating Ethanol's Alterations in Hepatic Steatosis and Oxidative Stress.Antioxidants (Basel, Switzerland) · 2026Article
- Proteomic signatures of life's essential 8 and incident atrial fibrillation among individuals with chronic kidney disease.Nutrition & metabolism · 2026Article
- Liver specific-inhibition of LPCAT3 ameliorates metabolic dysfunction-associated steatotic liver disease.Journal of molecular medicine (Berlin, Germany) · 2026Article
- Gut fungi exacerbates gallstone formation by activating neutrophil extracellular traps in the liver.Apoptosis : an international journal on programmed cell death · 2026Article
- Research progress on targeted regulatory proteins in the prevention and treatment of atherosclerosis.Frontiers in immunology · 2026Review
- Identification of intestinal enteroendocrine cell subtypes and their associated hormones in zebrafish.PLoS biology · 2025Article
- From model to man: Understanding Tregs' dual role in MASLD.JHEP reports : innovation in hepatology · 2025Article
- R-spondin 2 suppresses hepatic steatosis via activation of AMPK-ACC signaling.JHEP reports : innovation in hepatology · 2025Article
- Dynamic and Homeostatic Neuron-Astrocyte Interactions at GABAergic Synapses.Neurochemical research · 2025Review
- Angptl4 is upregulated by microenvironmental factors during the wound healing process and promotes epidermal stem cell proliferation via PRL8a6.Acta biochimica et biophysica Sinica · 2025Article
- Assessing the impact of perfluoroalkyl substances on liver health: a comprehensive study using multi-donor human liver spheroids.Environment international · 2025Article
- ANGPTL4: A Comprehensive Review of 25 Years of Research.Cancers · 2025Review
- Osteoclast-derived arachidonic acid triggers dormant lung adenocarcinoma cell activation.iScience · 2025Article
- Metabolic reprogramming by endothelial ANGPTL4 depletion protects against diabetic kidney disease.bioRxiv : the preprint server for biology · 2025Article
- Evaluating the Cardiometabolic Efficacy and Safety of Lipoprotein Lipase Pathway Targets in Combination With Approved Lipid-Lowering Targets: A Drug Target Mendelian Randomization Study.Circulation. Genomic and precision medicine · 2025Article
- Sexually Dimorphic Effects of CYP2B6 in the Development of Fasting-Mediated Steatosis in Mice: Role of the Oxylipin Products 9-HODE and 9-HOTrE.Biomedicines · 2025Article
2 more citing papers are in PubMed but not listed here.
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Authors and funding
14 authors at 2 institutions in 1 country.
Funding
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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