Inhibition of MAP4K4 signaling initiates metabolic reprogramming to protect hepatocytes from lipotoxic damage

• The primary hepatic consequence of obesity is non-alcoholic fatty liver disease (NAFLD), affecting about 25% of the global adult population. Non-alcoholic steatohepatitis (NASH) is a severe form of NAFLD characterized by liver lipid accumulation, inflammation, and hepatocyte ballooning, with a different degree of hepatic fibrosis. In the light of rapidly increasing prevalence of NAFLD and NASH, there is an urgent need for improved understanding of the molecular pathogenesis of these diseases. The aim of this study was to decipher the possible role of STE20-type kinase MAP4K4 in the regulation of he-patocellular lipotoxicity and susceptibility to NAFLD. We found that MAP4K4 mRNA expression in human liver biopsies was positively correlated with key hallmarks of NAFLD (i.e., liver steatosis, lobular inflammation, hepatocellular ballooning, and fibrosis). We also found that the silencing of MAP4K4 suppressed lipid deposition in human he-patocytes by stimulating beta-oxidation and tri-acylglycerol secretion, while attenuating fatty acid influx and lipid synthesis. Furthermore, down -regulation of MAP4K4 markedly reduced the glycolysis rate and lowered incidences of oxidative/ endoplasmic reticulum stress. In parallel, we observed suppressed JNK and ERK and increased AKT phosphorylation in MAP4K4-deficient hep-atocytes. Together, these results provide the first experimental evidence supporting the potential involvement of STE20-type kinase MAP4K4 as a component of the hepatocellular lipotoxic milieu promoting NAFLD susceptibility.

Ämnesord

NATURVETENSKAP  -- Biologi -- Biokemi och molekylärbiologi (hsv//swe)

NATURAL SCIENCES  -- Biological Sciences -- Biochemistry and Molecular Biology (hsv//eng)

Nyckelord

non-alcoholic fatty liver disease

non-alcoholic steatohepatitis

liver

steatosis

hepatic lipid metabolism

hepatic glycolysis

liver

inflammation

oxidative

endoplasmic reticulum stress

hepatic fibrosis

nonalcoholic steatohepatitis

insulin-resistance

family kinases

liver

stk25

expression

association

invasion

adhesion

glucose

Biochemistry & Molecular Biology

Publikations- och innehållstyp

ref (ämneskategori)

art (ämneskategori)