A High-Fat Diet Attenuates AMPK α1 in Adipocytes to Induce Exosome Shedding and Nonalcoholic Fatty Liver Development In Vivo

Abstract

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 AMPKα1-floxed (Prkaα1 fl/fl /wild-type [WT]), Prkaα1 −/− , liver tissue-specific Prkaα1 −/− , or AT-specific Prkaα1 −/− modification. In cultured adipocytes and white AT, 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 AT-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.

Lipid-induced DRAM recruits STOM to lysosomes and induces LMP to promote exosome release from hepatocytes in NAFLD

“…Loss of sirtuin 1 was revealed to inhibit the acidification of lysosomes, lead to impaired function of lysosomes, and promote the secretion of exosomes ( 18 ). Yan et al ( 36 ) showed that AMPKα1 could regulate the secretion of exosomes by inhibiting tumor susceptibility 101 (TSG101) expression. In this study, our results showed that DRAM could also promote the secretion of exosomes from hepatic cells in vitro and in vivo.…”

Integrative biology of extracellular vesicles in diabetes mellitus and diabetic complications

“…Disruption of these cellular biological processes is involved in the pathogenesis of DM. Lipotoxicity, a common risk factor for IR and T2D, can induce TSG101 expression in adipocytes and thus promote the biogenesis of exosomes 216 . Subsequently, TSG101 upregulation triggers the sorting of CD36 into EVs, which then are delivered into hepatocytes and evoke hepatic lipid accumulation 216 .…”

trans‐ferulic acid attenuates hyperglycemia‐induced oxidative stress and modulates glucose metabolism by activating AMPK signaling pathway in vitro

“…It has been reported that over production of superoxide by the mitochondrial electron-transport chain, causes diabetic complications (Brownlee, 2001;Jiang et al, 2021). Skeletal muscle and liver is the main site where AMPK functions as a fuel sensor in which ~60%-75% of glucose uptake and oxidation takes place in the body and it plays a major role in glucose and lipid metabolism (Yan et al, 2021; Yoshitomi et al, 2017). Thus, in the present study, we used HepG2 (human hepatocyte) and L6 (rat skeletal muscle cell) cells to explore the activation of AMPK by hydroxycinnamic acid derivatives under hyperglycemic condition.…”