P38γ modulates the lipid metabolism in non-alcoholic fatty liver disease by regulating the JAK-STAT signaling pathway.

Non-alcoholic fatty liver disease (NAFLD) is a major health problem in Western countries and has become the most common cause of chronic liver disease. Although NAFLD is closely associated with obesity, inflammation, and insulin resistance, its pathogenesis remains unclear. The disease begins with excessive accumulation of triglycerides in the liver, which in turn leads to liver cell damage, steatosis, inflammation, and so on. P38γ is one of the four isoforms of P38 mitogen-activated protein kinases (P38 MAPKs) that contributes to inflammation in different diseases. In this research, we investigated the role of P38γ in NAFLD. In vivo, a NAFLD model was established by feeding C57BL/6J mice with a methionine- and choline-deficient (MCD) diet and adeno-associated virus (AAV9-shRNA-P38γ) was injected into C57BL/6J mice by tail vein for knockdown P38γ. The results indicated that the expression level of P38γ was upregulated in MCD-fed mice. Furthermore, the downregulation of P38γ significantly attenuated liver injury and lipid accumulation in mice. In vitro, mouse hepatocytes AML-12 were treated with free fatty acid (FFA). We found that P38γ was obviously increased in FFA-treated AML-12 cells, whereas knockdown of P38γ significantly suppressed lipid accumulation in FFA-treated AML-12 cells. Furthermore, P38γ regulated the Janus Kinase-Signal transducers and activators of transcription (JAK-STAT) signaling pathway. Inhibition of P38γ can inhibit the JAK-STAT signaling pathway, thereby inhibiting lipid accumulation in FFA-treated AML-12 cells. In conclusion, our results suggest that targeting P38γ contributes to the suppression of lipid accumulation in fatty liver disease.

ZEB1 serves an oncogenic role in the tumourigenesis of HCC by promoting cell proliferation, migration, and inhibiting apoptosis via Wnt/ß-catenin signaling pathway.

Zinc finger E-box-binding homeobox 1 (ZEB1), a functional protein of zinc finger family, was aberrant expressed in many kinds of liver disease including hepatic fibrosis and Hepatitis C virus. Bioinformatics results showed that ZEB1 was abnormally expressed in HCC tissues. However, to date, the potential regulatory role and molecular mechanisms of ZEB1 are still unclear in the occurrence and development of HCC. This study demonstrated that the expression level of ZEB1 was significantly elevated both in liver tissues of HCC patients and cell lines (HepG2 and SMMC-7721 cells). Moreover, ZEB1 could promote the proliferation, migration, and invasion of HCC cells. On the downstream regulation mechanism, ZEB1 could activate the Wnt/ß-catenin signaling pathway by upregulating the protein expression levels of ß-catenin, c-Myc, and cyclin D1. Novel studies showed that miR-708 particularly targeted ZEB1 3'-UTR regions and inhibited the HCC cell proliferation, migration, and invasion. Furthermore, results of nude mice experiments of HCC model indicated that miR-708 could inhibit tumor growth and xenograft metastasis model was established to validate that miR-708 could inhibit HCC cell metastasis through tail-vein injection in vivo. Together, the study suggested that ZEB1 modulated by miR-708 might be a potential therapeutic target for HCC therapy.