Hepatocyte TGF-β Signaling Inhibiting WAT Browning to Promote NAFLD and Obesity Is Associated With Let-7b-5p.
Hepatocyte TGF-β Signaling Inhibiting WAT Browning to Promote NAFLD and Obesity Is Associated With Let-7b-5p.
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DOI：
10.1002/hep4.1892
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发表时间：
2022-06
影响因子：
5.1
通讯作者：
中科院分区：
文献类型：
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肝细胞中的转化生长因子β（TGF-β）信号传导促进脂肪变性和体重增加。然而，肝细胞中TGF-β信号传导促进非酒精性脂肪性肝病（NAFLD）病理性体重增加的过程尚未完全了解。在肝细胞特异性TGF-β受体II缺陷型（Tgfbr 2 ΔHEP）和Tgfbr 2flox/flox小鼠中，通过喂食高脂饮食（HFD）16周诱导肥胖和NAFLD。此外，通过给予CL-316，243（一种β3-肾上腺素能激动剂）或冷暴露7天诱导白色脂肪组织（WAT）的布朗宁。与Tgfbr 2 flox/flox小鼠相比，Tgfbr 2 ΔHEP小鼠对脂肪变性和肥胖具有抵抗力。Tgfbr 2 ΔHEP小鼠的代谢变化是由于肝脏中线粒体氧化磷酸化增加和白色至米色脂肪转化所致。进一步的机制研究表明，在用棕榈酸和TGF-β刺激后，来源于肝细胞的外来体let-7 b-5 p显著升高。事实上，在HFD喂养的Tgfbr 2 ΔHEP小鼠的肝脏、血清外泌体、腹股沟WAT和附睾WAT中let-7 b-5 p水平较低。此外，3 T3-L1细胞内化肝细胞来源的外来体。体外实验表明，let-7 b-5 p过表达增加肝细胞脂肪酸转运并抑制脂肪细胞样细胞产热，而let-7 b-5 p抑制剂发挥相反的作用。结论：肝细胞TGF-β-let-7 b-5 p信号通过减少线粒体氧化磷酸化和抑制白色至米色脂肪转化促进HFD诱导的脂肪变性和肥胖。肝细胞TGF-β信号传导在代谢中的这种作用部分与外来体let-7 b-5 p相关。
Transforming growth factor beta (TGF‐β) signaling in hepatocytes promotes steatosis and body weight gain. However, processes that TGF‐β signaling in hepatocytes promote pathological body weight gain in nonalcoholic fatty liver disease (NAFLD) are incompletely understood. Obesity and NAFLD were induced by 16 weeks of feeding a high‐fat diet (HFD) in hepatocyte‐specific TGF‐β receptor II–deficient (Tgfbr2ΔHEP ) and Tgfbr2flox/flox mice. In addition, browning of white adipose tissue (WAT) was induced by administration of CL‐316,243 (a β3‐adrenergic agonist) or cold exposure for 7 days. Compared with Tgfbr2 flox/flox mice, Tgfbr2ΔHEP mice were resistant to steatosis and obesity. The metabolic changes in Tgfbr2ΔHEP mice were due to the increase of mitochondrial oxidative phosphorylation in the liver and white‐to‐beige fat conversion. A further mechanistic study revealed that exosomal let‐7b‐5p derived from hepatocytes was robustly elevated after stimulation with palmitic acid and TGF‐β. Indeed, let‐7b‐5p levels were low in the liver, serum exosomes, inguinal WAT, and epididymal WAT in HFD‐fed Tgfbr2ΔHEP mice. Moreover, 3T3‐L1 cells internalized hepatocyte‐derived exosomes. An in vitro experiment demonstrated that let‐7b‐5p overexpression increased hepatocyte fatty acid transport and inhibited adipocyte‐like cell thermogenesis, whereas let‐7b‐5p inhibitor exerted the opposite effects. Conclusion: Hepatocyte TGF‐β‐let‐7b‐5p signaling promotes HFD‐induced steatosis and obesity by reducing mitochondrial oxidative phosphorylation and suppressing white‐to‐beige fat conversion. This effect of hepatocyte TGF‐β signaling in metabolism is partially associated with exosomal let‐7b‐5p.
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影响因子：
64.5
作者：
Chen Y;Zeng X;Huang X;Serag S;Woolf CJ;Spiegelman BM
通讯作者：
Spiegelman BM
影响因子：
64.8
作者：
Murphy, Kevin G.;Bloom, Stephen R.
通讯作者：
Bloom, Stephen R.
DOI：
10.1111/j.1749-6632.2002.tb04706.x
发表时间：
2002-01-01
期刊：
CELL SIGNALING, TRANSCRIPTION, AND TRANSLATION AS THERAPEUTIC TARGETS
影响因子：
--
作者：
Farnier, C;Krief, S;Bazin, R
通讯作者：
Bazin, R
影响因子：
82.9
作者：
Bartelt A;Widenmaier SB;Schlein C;Johann K;Goncalves RLS;Eguchi K;Fischer AW;Parlakgül G;Snyder NA;Nguyen TB;Bruns OT;Franke D;Bawendi MG;Lynes MD;Leiria LO;Tseng YH;Inouye KE;Arruda AP;Hotamisligil GS
通讯作者：
Hotamisligil GS
影响因子：
4.6
作者：
Lee YS;Kim SY;Ko E;Lee JH;Yi HS;Yoo YJ;Je J;Suh SJ;Jung YK;Kim JH;Seo YS;Yim HJ;Jeong WI;Yeon JE;Um SH;Byun KS
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