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.

FIGURE 1

Domain structure and alignment of human GCKIII kinases. Sequences of MST3 (GenPept accession number NP_001027467), MST4 (GenPept accession number NP_057626), and STK25 (GenPept accession number NP_001258906) were aligned using Clustal Omega (1.2.2; Conway Institute UCD, Dublin, Ireland). Fully, partially, or not aligned sequences are shown in red, violet, or black, respectively. ATP, adenosine triphosphate.

FIGURE 2

STK25 associates with intrahepatocellular lipid droplets. Representative immunofluorescence images of oleate‐loaded immortalized human hepatocytes (IHHs) and liver sections from high fat–fed mice, where the merged images show colocalization of STK25 and lipid droplets. (Figure adapted from Refs. 70 and 74).

FIGURE 3

Hepatic expression of GCKIII kinases is positively correlated with nonalcoholic fatty liver disease (NAFLD) severity. Correlation between messenger RNA (mRNA) levels in human liver biopsies and the individual histological lesions of NAFLD Activity Score (NAS; A–C), the total NAS (D), and subjects with low versus high NAS (E). (F) Correlation between mRNA levels and hepatic fat content measured by magnetic resonance spectroscopy. RQ, relative quantification. (Figure combines results from several publications (, , and 75).

FIGURE 4

Proposed mechanisms through which GCKIII kinases control liver lipotoxicity. Silencing of MST3, MST4, or STK25 in human hepatocytes lowers fat storage by inhibiting lipid droplet anabolism through reduced triacylglycerol (TAG) synthesis, and by stimulating lipid droplet catabolism through enhanced β‐oxidation and very low–density lipoprotein (VLDL)–TAG secretion, resulting in protection against oxidative and endoplasmic reticulum (ER) stress. LD, lipid droplet. (Figure combines results from several publications (, , , and 75).

FIGURE 5

A schematic model: STK25 antagonism protects mice against diet‐induced nonalcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC) by suppressing lipotoxicity‐induced inflammatory and profibrotic responses, reducing hepatocellular ballooning and apoptosis, decreasing compensatory proliferation and epithelial–mesenchymal transition (EMT). (Figure combines results from several publications (, , , and 96).