GCKIII kinases in lipotoxicity: Roles in NAFLD and beyond

Abstract

Nonalcoholic fatty liver disease (NAFLD) is defined by excessive accumulation of lipid droplets within hepatocytes. The STE20-type kinases comprising the germinal center kinase III (GCKIII) subfamily -MST3, MST4, and STK25 -decorate intrahepatocellular lipid droplets and have recently emerged as critical regulators of the initiation and progression of NAFLD. While significant advancement has been made toward deciphering the role of GCKIII kinases in hepatic fat accumulation (i.e., steatosis) as well as the aggravation of NAFLD into its severe form nonalcoholic steatohepatitis (NASH), much remains to be resolved. This review provides a brief overview of the recent studies in patient cohorts, cultured human cells, and mouse models, which have characterized the function of MST3, MST4, and STK25 in the regulation of hepatic lipid accretion, meta-inflammation, and associated cell damage in the context of NAFLD/NASH. We also highlight the conflicting data and emphasize future research directions that are needed to advance our understanding of GCKIII kinases as potential targets in the therapy of NAFLD and its comorbidities. Conclusions: Several lines of evidence suggest that GCKIII proteins govern the susceptibility to hepatic lipotoxicity and that pharmacological inhibition of these kinases could mitigate NAFLD development and aggravation. Comprehensive characterization of the molecular mode-of-action of MST3, MST4, and STK25 in hepatocytes as well as extrahepatic tissues is important, especially in relation to their impact on carcinogenesis, to fully understand the efficacy as well as safety of GCKIII antagonism.

Molecular mechanisms involved in regulating protein activity and biological function of MST3

“…Mechanistic analysis revealed that a lack of MST3 in both cultured liver cells and the livers of animals after HFD activates the insulin signaling pathway downstream of IRS1 by inhibiting forkhead box (FOX)O1-mediated downregulation of genes encoding gluconeogenic enzymes [ 40 ]. In addition to the regulation of insulin signaling, studies have reported that MST3, MST4, and STK25 are exclusively localized around intracellular lipid droplets and increase fat accumulation in human hepatocytes as well as the initiation and progression of nonalcoholic fatty liver disease (NAFLD) [ 9 , 41 ]. Mice treated with antisense oligonucleotides (ASOs) targeting MST3 effectively ameliorated HFD-induced nonalcoholic fatty liver disease (NAFLD)-associated liver steatosis, inflammation, fibrosis, and hepatocellular damage [ 41 ].…”

STK25: a viable therapeutic target for cancer treatments?

“…Serine/threonine protein kinase 25 (STK25), a member of the GCKIII, has been identified as a critical regulator of ectopic lipid storage, glucose and insulin homeostasis, fibrosis, and meta-inflammation. In humans, STK25 is located on chromosome 2q37.3 [4]. The important role of STK25 is to participate in autophagy, cell polarity, cell apoptosis, and cell migration.…”

7‐Hydroxyflavone improves nonalcoholic fatty liver disease by acting on STK24

“…These kinases decorate lipid droplets in hepatic cells, and the expression of GCKIII kinases in the liver is associated with the severity of NAFLD. The suppression of STK24, MST4, and STK25 dramatically decreased intracellular lipid accumulation in human hepatocytes (Mahlapuu et al, 2022). STK24 promotes IL‐17‐mediated inflammation (Jiang et al, 2018) and is upregulated in human hepatocellular carcinoma tissues (Caputo et al, 2023).…”