Loss of core fucosylation reduces low-density lipoprotein receptor expression in hepatocytes by inducing PCSK9 production.

Abstract

Fucosylation is a type of glycosylation, a form of post-transcriptional regulation of proteins, involved in cancer and inflammation. It involves the attachment of a fucose residue to N-glycans, O-glycans, and glycolipids, which is catalyzed by a family of enzymes called fucosyltransferases (Futs). Among the many Futs, α-1,6-fucosyltransferase (Fut8) is the only enzyme that produces α-1,6-fucosylated oligosaccharides (core fucose). In the human liver, the expression and activity of Fut8 are frequently elevated during progression of chronic liver diseases. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a well-known negative regulator of the low-density lipoprotein receptor (LDLR). Here, we found that loss of core fucose in immortalized hepatocytes led to LDLR downregulation through a dramatic induction of PCSK9. We used the immortalized hepatocytes derived from Fut8 knockout mice or a Fut8 knockdown AML12 hepatocyte cell line. Using these cells, we investigated the effects of Fut8 on hepatocyte cholesterol influx. Both cell lines had reduced LDLR protein levels, resulting from marked increases in PCSK9 expression. Intracellular cholesterol levels were significantly lower and LDL cholesterol uptake was suppressed in Fut8-KO cells. Hepatocyte nuclear factor 1α accumulated in nuclei of Fut8-KO hepatocytes, which mediated increases in PCSK9 mRNA expression. Our findings demonstrated that loss of core fucosylation promoted degradation of LDLR and impaired cholesterol uptake, which is a novel mechanism that regulates cholesterol influx, suggesting that Fut8 might be a novel causative gene for familial hypercholesterolemia.

• Authors: Yoshihiro Kamada, Akiko Yamamoto, Anna Fujiyoshi, Masahiro Koseki, Koichi Morishita, Tatsuya Asuka, Shinji Takamatsu, Yasushi Sakata, Tetsuo Takehara, Naoyuki Taniguchi, Eiji Miyoshi
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 527 Issue 3 Pg. 682-688 (06 30 2020) ISSN: 1090-2104 [Electronic] United States
• PMID: 32423823 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 Elsevier Inc. All rights reserved.

Chemical References

• Receptors, LDL
• Fucose
• Pcsk9 protein, mouse
• Proprotein Convertase 9

Topics

• Animals
• Cells, Cultured
• Fucose (metabolism)
• Glycosylation
• Hepatocytes (metabolism)
• Mice
• Mice, Inbred C57BL
• Proprotein Convertase 9 (metabolism)
• Receptors, LDL (analysis, metabolism)