MKP1 promotes nonalcoholic steatohepatitis by suppressing AMPK activity through LKB1 nuclear retention

Abstract

Nonalcoholic steatohepatitis (NASH) is triggered by hepatocyte death through activation of caspase 6, as a result of decreased adenosine monophosphate (AMP)-activated protein kinase-alpha (AMPKα) activity. Increased hepatocellular death promotes inflammation which drives hepatic fibrosis. We show that the nuclear-localized mitogen-activated protein kinase (MAPK) phosphatase-1 (MKP1) is upregulated in NASH patients and in NASH diet fed male mice. The focus of this work is to investigate whether and how MKP1 is involved in the development of NASH. Under NASH conditions increased oxidative stress, induces MKP1 expression leading to nuclear p38 MAPK dephosphorylation and decreases liver kinase B1 (LKB1) phosphorylation at a site required to promote LKB1 nuclear exit. Hepatic deletion of MKP1 in NASH diet fed male mice releases nuclear LKB1 into the cytoplasm to activate AMPKα and prevents hepatocellular death, inflammation and NASH. Hence, nuclear-localized MKP1-p38 MAPK-LKB1 signaling is required to suppress AMPKα which triggers hepatocyte death and the development of NASH.

Salusin‑α alleviates lipid metabolism disorders via regulation of the downstream lipogenesis genes through the LKB1/AMPK pathway

“…Given that Salusin-α may exert an inhibitory effect on lipid accumulation in HepG2 cells through the LKB1/AMPK signaling pathway, the mRNA expression levels of LKB1, AMPK, SREBP-1c, ACC and FASN (all members of the pathway), as well as the protein expression levels of p-LKB1, LKB1, p-AMPK, AMPK, SREBP1 and FASN were determined. AMPK, a crucial regulator of metabolism and mitochondrial homeostasis, could be activated through LKB1, which is a key upstream kinase, whereas SREBPs, of which there are three isoforms in mammalian cells (SREBP-1a, -1c, and -2), are major regulators of lipid metabolism that regulate lipid oxidation and catabolism ( 35 ). Additionally, SREBP-1c, which primarily governs the synthesis of fatty acids, can be activated by AMPK at the serine (Ser)372 site, leading to the inhibition of the translocation of SREBP-1c into the nucleus, thus regulating TG synthesis ( 36 - 38 ).…”