Abstract
Metabolic associated fatty liver disease (MAFLD) is associated with obesity, type 2 diabetes mellitus, and other metabolic syndromes. Farnesoid X receptor (FXR, NR1H4) plays a prominent role in hepatic lipid metabolism. This study combined the expression of liver genes in FXR knockout (KO) mice and MAFLD patients to identify new pathogenic pathways for MAFLD based on genome-wide transcriptional profiling. In addition, the roles of new target genes in the MAFLD pathogenic pathway were also explored. Two groups of differentially expressed genes were obtained from FXR-KO mice and MAFLD patients by transcriptional analysis of liver tissue samples. The similarities and differences between the two groups of differentially expressed genes were analyzed to identify novel pathogenic pathways and target genes. After the integration analysis of differentially expressed genes, we identified 134 overlapping genes, many of which have been reported to play an important role in lipid metabolism. Our unique analysis method of comparing differential gene expression between FXR-KO mice and patients with MAFLD is useful to identify target genes and pathways that may be strongly implicated in the pathogenesis of MAFLD. The overlapping genes with high specificity were screened using the Gene Expression Omnibus (GEO) database. Through comparison and analysis with the GEO database, we determined that BHMT2 and PKLR could be highly correlated with MAFLD. Clinical data analysis and RNA interference testing in vitro confirmed that BHMT2 may a new regulator of lipid metabolism in MAFLD pathogenesis. These results may provide new ideas for understanding the pathogenesis of MAFLD and thus provide new targets for the treatment of MAFLD.
Highlights
Metabolic-associated fatty liver disease (MAFLD), formerly known as non-alcoholic fatty liver disease (NAFLD), is the most common among chronic liver diseases
A shown in Figure 1C, the degree of steatosis and the ballooning of fat droplets were intensified in FXR–/– Metabolic associated fatty liver disease (MAFLD) mice compared to WT MAFLD mice
Consistent with a previous study, inhibition of FXR increased the degree of steatosis in animal models of MAFLD (Ma et al, 2013), which indicated inhibition of FXR was involved in the pathogenesis of MAFLD
Summary
Metabolic-associated fatty liver disease (MAFLD), formerly known as non-alcoholic fatty liver disease (NAFLD), is the most common among chronic liver diseases. It is diagnosed based on histological evaluation (biopsy), imaging studies, or blood biomarker evidence of fat accumulation in the liver (hepatic steatosis), in addition to one of the following three criteria overweight/obesity, presence of type 2 diabetes mellitus (T2DM), or evidence of metabolic dysregulation (Eslam et al, 2020a). Most MAFLD patients have progressed from a simple steatosis to the more advanced form of the disease, which may lead to cirrhosis or hepatocellular carcinoma and liver decompensation. In addition to liver transplantation, there are no effective therapies for advanced MAFLD that have been approved by the Federal Drug Administration (FDA) or European Medicines Agency (EMA); it is crucial to explore the pathogenesis of MAFLD
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