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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 1

The loss of ANGPTL4 function in hepatocytes improves serum lipid profile.

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The loss of ANGPTL4 function in hepatocytes improves serum lipid profile...
(A) Analysis of human ANGPTL4 expression in different tissues using Genotype-Tissue Expression (GTEx) database. Liver is highlighted. TPM, transcript per million reads. (B) Schematic diagram illustrating the generation of hepatocyte-specific ANGPTL4 mutant (Hmut) mice. The construct is composed of a short flippase recombination enzyme (Flp) recognition target (FRT), reporter, and a Cre recombinase recognition target (loxP). Angptl4 exons 4–6 are flanked by the lox P site. Mice with the floxed allele were generated by crossing with flp recombinase-deleter mice (middle panel). Subsequently, these mice were bred with mice expressing Cre recombinase to produce tissue-specific Hmut mice (bottom panel). PCR amplification of Angptl4fl/fl mice displaying bands from both, 1, or none of the floxed alleles (right panel). (C) mRNA expression of Angptl4 in the liver of WT and Hmut mice. R.E., relative expression. (D) Fasted plasma TAG (left panel), TC (middle panel), and HDL-C (right panel) from overnight-fasted WT and Hmut mice fed CD for 2 months (n = 10–13). (E) Cholesterol (left panel) and TAG (right panel) content of FPLC-fractionated lipoproteins from pooled plasma of overnight-fasted WT and Hmut mice fed a CD for 2 months (n = 7). All data are represented as mean ± SEM. *P < 0.05; ***P < 0.001, comparing Hmut with WT mice using the unpaired t test.

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

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