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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 5

Genetic loss of ANGPTL4 in hepatocytes improves obesity and attenuates atherosclerosis.

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Genetic loss of ANGPTL4 in hepatocytes improves obesity and attenuates a...
(A) Body weight (B), plasma TAGs, and TC from overnight-fasted WT and Hmut mice fed a WD for 16 weeks. (C) Lipoprotein profile analysis of pooled plasma of overnight-fasted WT and Hmut mice (n = 5). (D) Left: representative histological analysis of a cross section of the aortic root sinus isolated from WT and Hmut mice fed a WD for 16 weeks stained with H&E (upper panels) and oil red O (lower panels). Right: quantification of plaque size and the percentage area of neutral lipid accumulation calculated from H&E or ORO cross sections, respectively. Original magnification, ×10. (E) Representative cross-section analysis of macrophage content (CD68-positive cells) of the aortic root from WT and Hmut mice fed a WD for 16 weeks. Quantifications of the graphs on the right. Original magnification, ×10. All data are represented as mean ± SEM. *P < 0.05; **P < 0.01, comparing Hmut with WT mice using the unpaired t test.

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

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