Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Alerts
  • Advertising
  • Job board
  • Subscribe
  • Contact
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Author's Takes
  • Reviews
    • View all reviews ...
    • Immune Environment in Glioblastoma (Feb 2023)
    • Korsmeyer Award 25th Anniversary Collection (Jan 2023)
    • Aging (Jul 2022)
    • Next-Generation Sequencing in Medicine (Jun 2022)
    • New Therapeutic Targets in Cardiovascular Diseases (Mar 2022)
    • Immunometabolism (Jan 2022)
    • Circadian Rhythm (Oct 2021)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Commentaries
    • Research letters
    • Letters to the editor
    • Editorials
    • Viewpoint
    • Top read articles
  • Clinical Medicine
  • JCI This Month
    • Current issue
    • Past issues

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Author's Takes
  • In-Press Preview
  • Commentaries
  • Research letters
  • Letters to the editor
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Alerts
  • Advertising
  • Job board
  • Subscribe
  • Contact
Hepatocyte-specific suppression of ANGPTL4 improves obesity-associated diabetes and mitigates atherosclerosis in mice
Abhishek K. Singh, … , Yajaira Suárez, Carlos Fernández-Hernando
Abhishek K. Singh, … , Yajaira Suárez, Carlos Fernández-Hernando
Published July 13, 2021
Citation Information: J Clin Invest. 2021;131(17):e140989. https://doi.org/10.1172/JCI140989.
View: Text | PDF
Research Article Hepatology Metabolism

Hepatocyte-specific suppression of ANGPTL4 improves obesity-associated diabetes and mitigates atherosclerosis in mice

  • Text
  • PDF
Abstract

Hepatic uptake and biosynthesis of fatty acids (FAs), as well as the partitioning of FAs 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-induced 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 occur via increased HL activity. Notably, this inhibition strategy does not cause any of the deleterious effects previously observed with neutralizing antibodies.

Authors

Abhishek K. Singh, Balkrishna Chaube, Xinbo Zhang, Jonathan Sun, Kathryn M. Citrin, Alberto Canfrán-Duque, Binod Aryal, Noemi Rotllan, Luis Varela, Richard G. Lee, Tamas L. Horvath, Nathan L. Price, Yajaira Suárez, Carlos Fernández-Hernando

×

Figure 8

Inhibition of ROS-dependent activation of AMPK in Hmut mice reverses hepatic lipid metabolism.

Options: View larger image (or click on image) Download as PowerPoint
Inhibition of ROS-dependent activation of AMPK in Hmut mice reverses hep...
Eight-week-old Hmut mice were divided randomly into 3 groups. Each group of mice was administered with vehicle control (V), CompC, and NAC, respectively, for 3 consecutive days. (A and B) Determination of cellular ROS (H2O2 and O2–) in the hepatocytes isolated from the Hmut mice with indicated treatment groups. (C) Immunoblots showing the levels of p-AMPK, AMPK, p-ACC, and ACC in the liver isolated from fasted Hmut mice from indicated treatment groups. Lower panel shows image quantification of p-AMPK/AMPK, p-ACC/ACC, and ACC/HSP90 ratios from immunoblot densitometry. (D) FAO in liver of fasted Hmut mice from indicated treatment groups. (E) mRNA expression profile of FAO genes. (F and G) FASN and HMGCR enzymatic activity in the liver. (H) FA biosynthesis genes in the liver of mice administered with indicated inhibitors, as assessed by qRT-PCR. All data are represented as mean ± SEM. *P < 0.05, WT versus Hmut mice; **P < 0.01, WT versus Hmut mice; ***P < 0.001, WT versus Hmut mice; $P < 0.05, Hmut-Ctrl versus Hmut-NAC; $$P < 0.01, Hmut-Ctrl versus Hmut-NAC; $$$P < 0.001, Hmut-Ctrl versus Hmut-NAC; #P < 0.05, Hmut-Ctrl versus Hmut-CompC; ##P < 0.01, Hmut-Ctrl versus Hmut-CompC; ###P < 0.001, Hmut-Ctrl versus Hmut-CompC. P values were determined by 1-way ANOVA followed by Bonferroni’s post hoc analysis. (I) Proposed mechanism for the role of liver-derived ANGPTL4 in hepatic lipid metabolism.

Copyright © 2023 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts