Hepatic exosome-derived miR-130a-3p attenuates glucose intolerance via suppressing PHLPP2 gene in adipocyte.

Glucose and lipid metabolism disorders are a major risk factor for type II diabetes and cardiovascular diseases. Evidence has indicated that the interplay between the liver and adipose tissue is crucial in maintaining energy homeostasis. Recently, the interaction between two distant endocrine organs mainly focuses on the regulation of hormones and receptors. However, as a novel carrier in the inter-tissue communication, exosomes plays a role in liver-fat crosstalk, but its effects on glucose and lipid metabolisms are still unclear. In this study, we sought to investigate the effects of hepatic exosome-derived miR-130a-3p in the regulation of glucose/lipid metabolism in adipose tissues. In vivo, we constructed generalized miR-130a-3p knockout (130KO) and overexpressed (130OE) mice. Wild type (WT), 130KO and 130OE mice (n = 10) were assigned to a randomized controlled trial and were fed diets with either 10% (standard diet, SD) or 60% (high-fat diet, HFD) of total calories from fat (lard). Next, hepatic exosomes were extracted from WT-SD, 130KO-SD and 130OE-SD mice (WT-EXO, KO-EXO, OE-EXO), and 130KO mice were injected with 100 mg hepatic exosomes of different sources via tail-vein (once every 48 h) for 28 days, fed with HFD. In vitro, 3T3-L1 cells were treated with miR-130a-3p mimics, inhibitor and hepatic exosomes. Growth performance and glucose and lipid metabolic profiles were examined. After feeding with HFD, the weights of 130KO mice were markedly higher than WT mice. Over-expression of miR-130a-3p in 130OE mice and intravenous injection of 130OE-EXO in 130KO mice contributed to a positive correlation with the recovery of insulin resistance. In addition, miR-130a-3p mimics and 130OE-EXO treatment of 3T3-L1 cells exhibited decreasing generations of lipid droplets and increasing glucose uptake. Conversely, inhibition of miR-130a-3p in vitro and in vivo resulted in opposite phenotype changes. Furthermore, PHLPP2 was identified as a direct target of miR-130a-3p, and the hepatic exosome-derived miR-130a-3p could improve glucose intolerance via suppressing PHLPP2 to activate AKT-AS160-GLUT4 signaling pathway in adipocytes. We demonstrated that hepatic exosome-derived miR-130a regulated energy metabolism in adipose tissues, and elucidated a new molecular mechanism that hepatic exosome-derived miR-130a-3p is a crucial participant in organismic energy homeostasis through mediating crosstalk between the liver and adipose tissues.

Wu J ，Dong T ，Chen T ，Sun J ，Luo J ，He J ，Wei L ，Zeng B ，Zhang H ，Li W ，Liu J ，Chen X ，Su M ，Ni Y ，Jiang Q ，Zhang Y ，Xi Q ... -  《-》

Adipocyte PHLPP2 inhibition prevents obesity-induced fatty liver.

Kim K ，Kang JK ，Jung YH ，Lee SB ，Rametta R ，Dongiovanni P ，Valenti L ，Pajvani UB ... -  《Nature Communications》

Exosomal transfer of obesity adipose tissue for decreased miR-141-3p mediate insulin resistance of hepatocytes.

Dang SY ，Leng Y ，Wang ZX ，Xiao X ，Zhang X ，Wen T ，Gong HZ ，Hong A ，Ma Y ... -  《International Journal of Biological Sciences》

Mir-338-3p Mediates Tnf-A-Induced Hepatic Insulin Resistance by Targeting PP4r1 to Regulate PP4 Expression.

Insulin resistance is a critical factor contributing to the pathogenesis of type 2 diabetes and other metabolic diseases. Recent studies have indicated that miR-338-3p plays an important role in cancer. Here, we investigated whether miR-338-3p mediates tumour necrosis factor-α (TNF-α)-induced hepatic insulin resistance. The activation of the insulin signalling pathway and the level of glycogenesis were examined in the livers of the db/db and high fat diet (HFD)-fed mice and in HEP1-6 cells transfected with miR-338-3p mimic or inhibitor. Computational prediction of microRNA target, luciferase assay and Western blot were used to assess the miR-338-3p target. Chromatin immunoprecipitation (ChIP) assay was used to determine the transcriptional regulator of miR-338-3p. miR-338-3p was down-regulated in the livers of the db/db, HFD-fed and TNF-α-treated C57BL/6J mice, as well as in mouse HEP1-6 hepatocytes treated with TNF-α. Importantly the down-regulation of miR-338-3p induced insulin resistance, as indicated by impaired glucose tolerance and insulin tolerance. Further research showed that the down-regulated miR-338-3p resulted in the impaired AKT/ glycogen synthase kinase 3 beta (GSl·Gβ) signalling pathway and glycogen synthesis. In contrast, hepatic over-expression of miR-338-3p rescued the TNF-α-induced insulin resistance. Moreover, protein phosphatase 4 regulator subunit 1 (PP4R1) was identified as a direct target of miR-338-3p that mediated hepatic insulin signalling by regulating protein phosphatase 4 (PP4). Finally we identified hepatic nuclear factor 4 alpha (HNF-4α) as the transcriptional regulator of miRNA-338-3p. Our studies provide novel insight into the critical role and molecular mechanism by which miR-338-3p is involved in TNF-α-induced hepatic insulin resistance. miR-338-3p might mediate TNF-α-induced hepatic insulin resistance by targeting PP4R1 to regulate PP4 expression.

Dou L ，Wang S ，Sun L ，Huang X ，Zhang Y ，Shen T ，Guo J ，Man Y ，Tang W ，Li J ... -  《-》

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

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.

Yan C ，Tian X ，Li J ，Liu D ，Ye D ，Xie Z ，Han Y ，Zou MH ... -  《-》