Lipid droplet-associated kinase STK25 regulates peroxisomal activity and metabolic stress response in steatotic liver

Abstract

Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) are emerging as leading causes of liver disease worldwide and have been recognized as one of the major unmet medical needs of the 21st century. Our recent translational studies in mouse models, human cell lines, and well-characterized patient cohorts have identified serine/threonine kinase (STK)25 as a protein that coats intrahepatocellular lipid droplets (LDs) and critically regulates liver lipid homeostasis and progression of NAFLD/NASH. Here, we studied the mechanism-of-action of STK25 in steatotic liver by relative quantification of the hepatic LD-associated phosphoproteome from high-fat diet-fed Stk25 knockout mice compared with their wild-type littermates. We observed a total of 131 proteins and 60 phosphoproteins that were differentially represented in STK25-deficient livers. Most notably, a number of proteins involved in peroxisomal function, ubiquitination-mediated proteolysis, and antioxidant defense were coordinately regulated in Stk25−/− versus wild-type livers. We confirmed attenuated peroxisomal biogenesis and protection against oxidative and ER stress in STK25-deficient human liver cells, demonstrating the hepatocyte-autonomous manner of STK25’s action. In summary, our results suggest that regulation of peroxisomal function and metabolic stress response may be important molecular mechanisms by which STK25 controls the development and progression of NAFLD/NASH.

Silencing of STE20‐type kinase MST3 in mice with antisense oligonucleotide treatment ameliorates diet‐induced nonalcoholic fatty liver disease

“…[60][61][62] We have also recently identified STE20-type kinase STK25, localized to intracellular lipid droplets in mouse and human hepatocytes, as a critical regulator of diet-induced NAFLD initiation and progression. [10][11][12][13][14][15][16] Here, we demonstrate that pharmacological inhibition of lipid droplet-decorating STE20-type kinase MST3 in obese mice reprograms hepatic metabolism and restrains all measured manifestations of NAFLD, including liver steatosis, inflammation, fibrosis, and hepatocellular injury. Our study emphasizes the importance of lipid droplet proteins in overnutrition-mediated NAFLD and warrants further investigations to assess whether the beneficial effects of MST3 antagonism observed in mice will translate to humans.…”

“…10,11 Furthermore, our recent translational investigations in genetic mouse models, human cell lines, and well-characterized patient cohorts have identified STK25 as a critical regulator of intrahepatocellular lipid droplet dynamics and NAFLD/NASH progression. [10][11][12][13][14][15][16] The aim of this study was to explore whether pharmacological inhibition of MST3 signaling in mice by using Mst3targeting antisense oligonucleotides (ASOs) can promote hepatic lipid clearance and mitigate diet-induced NAFLD progression in vivo. Antisense technology is a powerful therapeutic platform consisting of oligonucleotide analogs that can specifically degrade a target mRNA by forming an mRNA-ASO duplex, which then serves as a substrate for the ubiquitously expressed RNase H1 endonuclease.…”

Oxidative Stress in NAFLD: Role of Nutrients and Food Contaminants

“…ER stress also modulates expression of proteins involved in lipid and glucose metabolism, thus contributing directly to hepatic lipid accumulation [ 262 ]. Finally, in addition to mitochondria and ER, the peroxisomes, which are important in H 2 O 2 production by peroxisomal FA oxidation, contribute to oxidative stress in NAFLD ( Figure 3 ) [ 226 , 237 , 238 , 263 ].…”

Depletion of protein kinase STK25 ameliorates renal lipotoxicity and protects against diabetic kidney disease

“…Impaired renal peroxisomal function has been shown to increase ROS production in several studies ( 45 , 46 ); however, here we found that lower peroxisomal biogenesis in STK25-deficient kidney cells clearly correlated with substantially reduced oxidative damage. Notably, our recent studies using global proteomic analysis also revealed that a number of proteins involved in peroxisomal function, including mediators of peroxisomal fatty acid transport, metabolism, and β-oxidation, are coordinately suppressed in the livers from high-fat diet–fed Stk25 –/– mice, which is paralleled by alleviated ROS production and protection against hepatic inflammation, fibrosis, and cell damage ( 47 ). Thus, our data suggest that suppressed peroxisomal biogenesis — at least when paralleled with an increase in mitochondrial activity, as seen in STK25-deficient kidney and liver cells ( 11 , 18 ) — may result in reduced rather than increased oxidative stress.…”