Identification of MAP3K4 as a novel regulation factor of hepatic lipid metabolism in non-alcoholic fatty liver disease

Abstract

Background Non-alcoholic fatty liver disease (NAFLD) is a metabolic disorder with abnormal lipid metabolism. The present study was to identify regulatory genes related to lipid droplets (LDs) abnormal accumulation in NAFLD. Methods transcriptomic analysis and bioinformatics analysis (GEO database) were used to identify potential genes in abnormal lipid metabolism of NAFLD. A candidate gene MAP3K4 expression were detected by immunohistochemistry staining in NAFLD and controls. RNA interference and immunoblotting were used to verify the roles of MAP3K4 in the formation of hepatic LDs. Results A total of 134 candidate genes were screened, including 44 up-regulated genes and 90 down-regulated genes. 29 genes in the protein–protein interaction (PPI) were selected as hub genes, including MAP3K4. The expression levels of MAP3K4 were positively correlated with NAFLD activity score (r = 0.702, p = 0.002). Furthermore, we found a positive correlation of MAP3K4 expression with serum total cholesterol (r = 0.564, p = 0.023), uric acid levels (r = 0.520, p = 0.039), and body mass index (r = 0.574, p = 0.020). Downregulation of MAP3K4 decreased LDs accumulation in HepG2 cells and reduced the expression of CGI-58 and Plin-2 by imbibition of JNK and group IVA cytosolic phospholipase A2 (cPLA2) activation. Conclusion The study revealed a number of regulatory genes related to hepatic lipid metabolism of NAFLD, and demonstrated that MAP3K4 played a pivotal role in the hepatic lipogenesis of NAFLD.

Identification of metabolic biomarkers associated with nonalcoholic fatty liver disease

“…Immune disorders, intestinal imbalances, and metabolic disorders promote liver inflammation and other aspects during late-stage NAFLD [ 9 ]. A study has shown that inflammation and metabolic processes in adipose tissue could accelerate NASH development and serve as therapeutic targets [ 10 ]. In fact, some studies have suggested that NAFLD could be referred to as metabolic (dysfunction) associated fatty liver disease (MAFLD) [ 11 ].…”

Deciphering the role of alternative splicing as a potential regulator in fat-tail development of sheep: a comprehensive RNA-seq based study

“…A recent study has shown that CAMK2 regulates adipocyte lipolysis and its activity is increased in obese mice adipose tissue, which makes it a critical component of metabolic regulation in obesity 52 . Vital role of MAP3K4 (as an important member of the MAPK signaling pathway) in the hepatic lipogenesis of non-alcoholic fatty liver disease has been well described 53 . The expression of other important member of MAPK in the final DAS genes, MAP4K4, is reported to be increased during obesity, which makes it an important negative regulator of adipose lipogenesis in metabolic disease 54 .…”

ROS-induced ribosome impairment underlies ZAKα-mediated metabolic decline in obesity and aging

“…Indeed, a recent report described an independent role for the Zak gene in promoting stem cell plasticity in the small intestine of leucine-restricted mice ( 73 ). Further adding to the complexity of our current mouse model, the ZAKβ isoform is activated by volumetric cell compression and protects against muscle pathology in mice and humans ( 49 , 74 ), and this splice variant is also interrupted in the whole-body ZAK KO animals. For the present study, generation of mouse models for conditional KO of the Zakα isoform was not achieved.…”

“…Finally, we do not know to what extent our findings in mice can be extrapolated to humans. Patients with nonsense mutations in the common kinase domain of ZAKα and ZAKβ present with severe early-onset myopathy but with no reports of phenotypes of a metabolic nature ( 74 ). However, the feeding paradigm for mice used in this study is generally considered a good model of human obesity and associated metabolic complications.…”