Genetic Ablation of STE20-Type Kinase MST4 Does Not Alleviate Diet-Induced MASLD Susceptibility in Mice
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ABSTRACT:
SUBMITTER: Caputo M
PROVIDER: S-EPMC10888586 | biostudies-literature | 2024 Feb
REPOSITORIES: biostudies-literature
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Project description:Nonalcoholic fatty liver disease (NAFLD) has emerged as a leading cause of chronic liver disease worldwide, primarily because of the massive global increase in obesity. Despite intense research efforts in this field, the factors that govern the initiation and subsequent progression of NAFLD are poorly understood, which hampers the development of diagnostic tools and effective therapies in this area of high unmet medical need. Here we describe a regulator in molecular pathogenesis of NAFLD: STE20-type protein kinase MST4. We found that MST4 expression in human liver biopsies was positively correlated with the key features of NAFLD (i.e., hepatic steatosis, lobular inflammation, and hepatocellular ballooning). Furthermore, the silencing of MST4 attenuated lipid accumulation in human hepatocytes by stimulating β-oxidation and triacylglycerol secretion, while inhibiting fatty acid influx and lipid synthesis. Conversely, overexpression of MST4 in human hepatocytes exacerbated fat deposition by suppressing mitochondrial fatty acid oxidation and triacylglycerol efflux, while enhancing lipogenesis. In parallel to these reciprocal alterations in lipid storage, we detected substantially decreased or aggravated oxidative/endoplasmic reticulum stress in human hepatocytes with reduced or increased MST4 levels, respectively. Interestingly, MST4 protein was predominantly associated with intracellular lipid droplets in both human and rodent hepatocytes. Conclusion: Together, our results suggest that hepatic lipid droplet-decorating protein MST4 is a critical regulatory node governing susceptibility to NAFLD and warrant future investigations to address the therapeutic potential of MST4 antagonism as a strategy to prevent or mitigate the development and aggravation of this disease.
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Project description:ObjectiveNon-alcoholic fatty liver disease (NAFLD), the primary hepatic consequence of obesity, is affecting about 25% of the global adult population. The aim of this study was to examine the in vivo role of STE20-type protein kinase TAOK3, which has been previously reported to regulate hepatocellular lipotoxicity in vitro, in the development of NAFLD and systemic insulin resistance in the context of obesity.MethodsTaok3 knockout mice and wild-type littermates were challenged with a high-fat diet. Various in vivo tests were performed to characterize the whole-body metabolism. NAFLD progression in the liver, and lipotoxic damage in adipose tissue, kidney, and skeletal muscle were compared between the genotypes by histological assessment, immunofluorescence microscopy, protein and gene expression profiling, and biochemical assays. Intracellular lipid accumulation and oxidative/ER stress were analyzed in cultured human and mouse hepatocytes where TAOK3 was knocked down by small interfering RNA. The expression of TAOK3-related STE20-type kinases was quantified in different organs from high-fat diet-fed Taok3-/- and wild-type mice.ResultsTAOK3 deficiency had no impact on body weight or composition, food consumption, locomotor activity, or systemic glucose or insulin homeostasis in obese mice. Consistently, Taok3-/- mice and wild-type littermates developed a similar degree of high-fat diet-induced liver steatosis, inflammation, and fibrosis, and we detected no difference in lipotoxic damage of adipose tissue, kidney, or skeletal muscle when comparing the two genotypes. In contrast, the silencing of TAOK3 in vitro markedly suppressed ectopic lipid accumulation and metabolic stress in mouse and human hepatocytes. Interestingly, the hepatic mRNA abundance of several TAOK3-related kinases, which have been previously implicated to increase the risk of NAFLD susceptibility, was significantly elevated in Taok3-/- vs. wild-type mice.ConclusionsIn contrast to the in vitro observations, genetic deficiency of TAOK3 in mice failed to mitigate the detrimental metabolic consequences of chronic exposure to dietary lipids, which may be partly attributable to the activation of liver-specific compensation response for the genetic loss of TAOK3 by related STE20-type kinases.
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