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

Abstract

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.

Optimization of Neferine Purification Based on Response Surface Methodology and Its Anti-Metastasis Mechanism on HepG2 Cells

“…Hepatocellular carcinoma (HCC) is one of the most common cancers in the world due to its low five-year survival rate and high mortality rate, which brings a huge burden to the global medical system [ 5 ]. In molecular pathogenesis, dysregulation of key signaling pathways, i.e., Wnt/β-catenin, JAK/STAT, etc., strongly promotes the development of HCC [ 30 , 31 , 32 , 33 ]. Although significant progress has been made in the diagnosis and treatment of liver cancer, including radiotherapy [ 34 ], chemotherapy [ 35 ], and immunotherapy [ 36 ], and first-line clinical drugs have been introduced to treat advanced liver cancer [ 37 , 38 ], the prognosis of some HCC patients is not ideal, and their five-year survival rate is no more than 18% [ 5 ].…”

“…The cytotoxicity of Neferine was subsequently determined in HepG2 cells by the CCK-8 assay. Cells were treated with different concentrations of Neferine (16,32,48,64, and 80 µM) for 24, 48, 72, and 96 h (Figure 3). The IC 50 was shown to be 33.80, 29.47, 24.35, and 2.78 µM, respectively.…”

“…Cells were treated with various concentrations of Neferine (16,32,48,64, or 80 µM). Then, 100 µL of CCK-8 solution (10% CCK-8 and 90% DMEM) was added to each well after 24 h, 48 h, 72 h, or 96 h of culture, followed by an additional 2-4 h of incubation at 37 • C in a cell culture chamber.…”

NUP85 alleviates lipid metabolism and inflammation by regulating PI3K/AKT signaling pathway in nonalcoholic fatty liver disease

“…Mice liver tissues were obtained and immediately soaked it in general tissue fixative solution for 24 h (5 μm) 20 . The tissue was then photographed using an optical microscope.…”

p38γ MAPK Inflammatory and Metabolic Signaling in Physiology and Disease

“…Cardiac-specific p38γ/p38δ overexpression leads to glucose intolerance and insulin resistance, whereas early postnatal cardiac-specific p38γ and p38δ deletion increases cardiac glycogen storage and affects whole-body metabolism [ 39 ]. In addition, p38γ knockdown suppressed lipid accumulation by inhibiting the JAK-STAT pathway, suggesting that targeting p38γ may contribute to the suppression of lipid accumulation in fatty liver disease [ 40 ]. The results show that p38γ plays an important role in regulation of glucose and lipid metabolism in the heart, muscles, and liver.…”