title: High-fructose feeding promotes accelerated degradation of hepatic LDL receptor and hypercholesterolemia in hamsters via elevated circulating PCSK9 levels.
abstract: BACKGROUND
  High fructose diet (HFD) induces dyslipidemia and insulin resistance in experimental animals and humans with incomplete mechanistic understanding. By utilizing mice and hamsters as in vivo models, we investigated whether high fructose consumption affects serum PCSK9 and liver LDL receptor (LDLR) protein levels.
  
  
  RESULTS
  Feeding mice with an HFD increased serum cholesterol and reduced serum PCSK9 levels as compared with the mice fed a normal chow diet (NCD). In contrast to the inverse relationship in mice, serum PCSK9 and cholesterol levels were co-elevated in HFD-fed hamsters. Liver tissue analysis revealed that PCSK9 mRNA and protein levels were both reduced in mice and hamsters by HFD feeding, however, liver LDLR protein levels were markedly reduced by HFD in hamsters but not in mice. We further showed that circulating PCSK9 clearance rates were significantly lower in hamsters fed an HFD as compared with the hamsters fed NCD, providing additional evidence for the reduced hepatic LDLR function by HFD consumption. The majority of PCSK9 in hamster serum was detected as a 53 kDa N-terminus cleaved protein. By conducting in vitro studies, we demonstrate that this 53 kDa truncated hamster PCSK9 is functionally active in promoting hepatic LDLR degradation.
  
  
  CONCLUSIONS
  Our studies for the first time demonstrate that high fructose consumption increases serum PCSK9 concentrations and reduces liver LDLR protein levels in hyperlipidemic hamsters. The positive correlation between circulating cholesterol and PCSK9 and the reduction of liver LDLR protein in HFD-fed hamsters suggest that hamster is a better animal model than mouse to study the modulation of PCSK9/LDLR pathway by atherogenic diets.
authors: Department of Veterans Affairs Palo Alto Health Care System, Palo Alto, CA 94304, USA.
authors: Bin
authors: B
authors: Dong
authors: Department of Veterans Affairs Palo Alto Health Care System, Palo Alto, CA 94304, USA.
authors: Amar Bahadur
authors: AB
authors: Singh
authors: Department of Veterans Affairs Palo Alto Health Care System, Palo Alto, CA 94304, USA.
authors: Salman
authors: S
authors: Azhar
authors: Laboratory of Biochemical Neuroendocrinology, Clinical Research Institute of Montreal, Montreal, QC H2W 1R7, Canada.
authors: Nabil G
authors: NG
authors: Seidah
authors: Department of Veterans Affairs Palo Alto Health Care System, Palo Alto, CA 94304, USA. Electronic address: Jingwen.Liu@va.gov.
authors: Jingwen
authors: J
authors: Liu
mesh_terms: D000818:Animals; D002784:Cholesterol / Q000097:blood; D002851:Chromatography, High Pressure Liquid; D006224:Cricetinae; D004036:Diet, Atherogenic; D050171:Dyslipidemias / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D005632:Fructose / Q000737:chemistry*; D057809:HEK293 Cells; D006801:Humans; D007333:Insulin Resistance; D008099:Liver / Q000378:metabolism; D008297:Male; D008647:Mesocricetus; D051379:Mice; D008810:Mice, Inbred C57BL; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D011973:Receptors, LDL / Q000378:metabolism*; D012697:Serine Endopeptidases / Q000378:metabolism*
chemical_list: D011973:Receptors, LDL; D005632:Fructose; D002784:Cholesterol; C472126:Pcsk9 protein, mouse; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases
keywords: Dyslipidemia; Hamsters; High fructose diet; LDL receptor; PCSK9