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A High-Fat Diet Attenuates Amp-Activated Protein Kinase α1 in Adipocytes to Induce Exosome Shedding and Nonalcoholic Fatty Liver Development in Vivo

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posted on 02.12.2020, 06:45 by Ada Admin, Chenghui Yan, Xiaoxiang Tian, Jiayin Li, Dan Liu, Ding Ye, Zhonglin Xie, Yaling Han, Ming-Hui Zou
Exosomes are important for intercellular communication, but the role of exosomes in the communication between adipose tissue (AT) and the liver remains unknown. The aim of this study is to determine the contribution of AT-derived exosomes in nonalcoholic fatty liver disease (NAFLD). Exosome components, liver fat content, and liver function were monitored in AT in mice fed a high-fat diet (HFD) or treated with metformin- or GW4869 and with AMP-activated protein kinase (AMPKα1) floxed (Prkaα1fl/fl/WT), Prkaα1-/-, liver tissue-specific Prkaα1-/-, or AT-specific Prkaα1-/- modification. In cultured adipocytes and white adipose tissue (WAT), the absence of AMPKα1 increased exosome release and exosomal proteins by elevating tumor susceptibility gene 101 (TSG101)-mediated exosome biogenesis. In adipocytes treated with palmitic acid, TSG101 facilitated scavenger receptor class B (CD36) sorting into exosomes. CD36-containing exosomes were then endocytosed by hepatocytes to induce lipid accumulation and inflammation. Consistently, an HFD induced more severe lipid accumulation and cell death in Prkaα1-/- and adipose tissue-specific Prkaα1-/- mice than in WT and liver-specific Prkaα1-/- mice. AMPK activation by metformin reduced adipocyte-mediated exosome release and mitigated fatty liver development in WT and liver specific Prkaα1-/- mice. Moreover, administration of the exosome inhibitor GW4869 blocked exosome secretion and alleviated HFD-induced fatty livers in Prkaα1-/- and adipocyte-specific Prkaα1-/- mice. We conclude that HFD-mediated AMPKα1 inhibition promotes NAFLD by increasing numbers of AT CD36-containing exosomes.

Funding

This study was supported by National Science Funding of China (NSFC 81670276) to Dr. Han and National Science funding of China (NSFC 82070300) to Dr. Yan.

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