Janus kinase activation by cytokine oncostatin M decreases PCSK9 expression in liver cells

Abstract

This article is available online at http://www.jlr.org dation of LDL receptor (LDLR) ( 1-4 ). PCSK9 is a secreted protein expressed predominantly in the liver, small intestine, and kidney ( 1 ). It is synthesized as a ~72 kDa zymogen that undergoes intramolecular cleavage in the endoplasmic reticulum to form a heterodimer of a prosegment (122 amino acids) and a 60 kDa active form, which is secreted as a proteolytic inactive form ( 1, 5 ). In plasma, PCSK9 binds directly to the EGF-A extracellular domain of hepatic LDLR ( 6, 7 ). This binding and the subsequent internalization of the PCSK9-LDLR complex leads to the intracellular degradation of LDLR in lysosomes, thus increasing the level of circulating LDL-C. In humans, gainof-function mutations in PCSK9 result in autosomal hypercholesterolemia and premature atherosclerosis ( 8 ).Conversely, loss-of-function mutations within PCSK9 are associated with a reduction in plasma LDL-C and protection against coronary heart disease ( 9, 10 ).Investigations conducted in cell culture and animal models have demonstrated that the expression of PCSK9 is controlled at the transcriptional level. So far, two transcription factors have been identifi ed as critical players in PCSK9 gene transcription. PCSK9 is a target gene of sterol regulatory element binding protein (SREBP) ( 4, 11 ). Analogous to LDLR and other cholesterol-regulated genes, the proximal region of the PCSK9 promoter contains an SRE-1 motif ( 12 ), which interacts with the nuclear forms of SREBPs under the condition of depleted intracellular sterols. The second transactivator identifi ed for PCSK9 gene transcription is hepatic nuclear factor 1 a (HNF1 a ), which is abundantly expressed in liver. HNF1 a regulates Recent studies have identifi ed proprotein convertase subtilisin/kexin type 9 (PCSK9) as a critical new player in the control of plasma LDL cholesterol (LDL-C) levels through its role in mediating the posttranslational degraThis study was supported

Inhibition of PCSK9 Transcription by Berberine Involves Down-regulation of Hepatic HNF1α Protein Expression through the Ubiquitin-Proteasome Degradation Pathway

“…Anti-LDLR antibody was obtained from BioVision. Anti-hamster PCSK9 antibody was developed in our laboratory and was reported previously (19). Anti-human PCSK9 antibody was described previously (14).…”

Hepatic Cholesterol Homeostasis

“…In any case, these results imply more complicated regulatory pathways for PCSK9 in hepatocytes than are usually understood to exist. [30][31][32] IDOL is a liver X receptor nuclear receptor-regulated target, which mediates ubiquitination and targeted degradation of the LDL receptor. 33 IDOL is stimulated under conditions of high intracellular cholesterol but operates independently of SREBP2 regulation.…”

Regulation of lipid metabolism by obeticholic acid in hyperlipidemic hamsters

“…Anti-HNF4, anti-FASN, and anti-stearoyl-CoA desaturase (SCD)1 antibodies were purchased from Santa Cruz Biotechnology (Santa Cruz, CA). Antihamster PCSK9 antibody that recognizes the C-terminal end of hamster PCSK9 (CRNRPSAKASWVHQ) was developed in our laboratory and previously reported (28). Rabbit anti-sterol regulatory element-binding protein (SREBP)2 antibodies were generously provided by Dr. Sahng Wook Park (Yonsei University College of Medicine, Seoul, Korea) and were used as previously described (29).…”