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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.
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Research Article Hepatology Metabolism

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 (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

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Figure 9

GalNac-conjugated ANGPTL4 ASO treatment improves whole-body metabolism under physiological and pathophysiological conditions.

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GalNac-conjugated ANGPTL4 ASO treatment improves whole-body metabolism u...
(A) Schematic presentation of the experimental design of GalNac-conjugated ANGPTL4 ASO (ANGPTL4 ASO) treatment of CD-fed mice. (B) Angptl4 expression in eWAT and liver. (C) Plasma TAG, TC, and HDL-C from overnight-fasted 6-week Angptl4 ASO or Ctrl ASO–treated WT mice. (D) Fasting blood glucose. (E) Strategy for treatment of GalNac-conjugated ANGPTL4 ASO in fat-induced obese mice. HFD-fed mice were treated with Angptl4-ASO or Ctrl ASO for 6 weeks. (F) Body weight: number of weeks on an HFD diet is indicated (treatment was started at week 5 of HFD feeding). Inset represents fat mass measured by Echo-MRI. (G) Plasma TAG, TC, and HDL-C from overnight-fasted 6 -week ANGPTL4 ASO– or Ctrl ASO–treated HFD-fed WT mice. (H and I) Intraperitoneal glucose tolerance test and intraperitoneal insulin tolerance test in 6-week ANGPTL4 ASO– or Ctrl ASO–injected mice fed an HFD. Inset represents AUC. (J) Representative images of small intestine cross sections of HFD-fed mice from 10-week treatment of Angptl4 ASO or Ctrl ASO, stained with macrophage marker CD68 and H&E. Original magnification, ×20. (K) Activity of plasma ALT and AST after 10-week treatment of ANGPTL4 ASO or Ctrl ASO in HFD-induced obese mice. All data are represented as mean ± SEM. *P < 0.05; **P < 0.01; ***P < 0.001, comparing Angptl4 ASO– with Ctrl ASO–treated mice using unpaired t test.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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