Hepatocyte TGF-β Signaling Inhibiting WAT Browning to Promote NAFLD and Obesity Is Associated With Let-7b-5p

Transforming growth factor beta (TGF-beta) signaling in hepatocytes promotes steatosis and body weight gain. However, processes that TGF-beta 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-beta receptor II-deficient (Tgfbr2(Delta HEP)) and Tgfbr2(flox/flox) mice. In addition, browning of white adipose tissue (WAT) was induced by administration of CL-316,243 (a beta 3-adrenergic agonist) or cold exposure for 7 days. Compared with Tgfbr2 (flox/flox) mice, Tgfbr2(Delta HEP) mice were resistant to steatosis and obesity. The metabolic changes in Tgfbr2(Delta HEP) 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-beta. Indeed, let-7b-5p levels were low in the liver, serum exosomes, inguinal WAT, and epididymal WAT in HFD-fed Tgfbr2(Delta HEP) 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-beta-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-beta signaling in metabolism is partially associated with exosomal let-7b-5p.

Automated summary

TGF-beta signaling in hepatocytes promotes steatosis and body weight gain, and its specific role in NAFLD is not fully understood. The study found that hepatocyte TGF-beta signaling can promote obesity and fatty liver induced by a high-fat diet by regulating mitochondrial oxidative phosphorylation and suppressing white-to-beige fat conversion. It was also found that let-7b-5p derived from hepatocyte-secreted exosomes plays an important role in this process.