title: Proprotein convertase subtilisin kexin type 9 promotes intestinal overproduction of triglyceride-rich apolipoprotein B lipoproteins through both low-density lipoprotein receptor-dependent and -independent mechanisms.
abstract: BACKGROUND
  Proprotein convertase subtilisin kexin type 9 (PCSK9) promotes the degradation of the low-density lipoprotein (LDL) receptor (LDLR), and its deficiency in humans results in low plasma LDL cholesterol and protection against coronary heart disease. Recent evidence indicates that PCSK9 also modulates the metabolism of triglyceride-rich apolipoprotein B (apoB) lipoproteins, another important coronary heart disease risk factor. Here, we studied the effects of physiological levels of PCSK9 on intestinal triglyceride-rich apoB lipoprotein production and elucidated for the first time the cellular and molecular mechanisms involved.
  
  
  RESULTS
  Treatment of human enterocytes (CaCo-2 cells) with recombinant human PCSK9 (10 μg/mL for 24 hours) increased cellular and secreted apoB48 and apoB100 by 40% to 55% each (P<0.01 versus untreated cells), whereas short-term deletion of PCSK9 expression reversed this effect. PCSK9 stimulation of apoB was due to a 1.5-fold increase in apoB mRNA (P<0.01) and to enhanced apoB protein stability through both LDLR-dependent and LDLR-independent mechanisms. PCSK9 decreased LDLR protein (P<0.01) and increased cellular apoB stability via activation of microsomal triglyceride transfer protein. PCSK9 also increased levels of the lipid-generating enzymes FAS, SCD, and DGAT2 (P<0.05). In mice, human PCSK9 at physiological levels increased intestinal microsomal triglyceride transfer protein levels and activity regardless of LDLR expression.
  
  
  CONCLUSIONS
  PCSK9 markedly increases intestinal triglyceride-rich apoB production through mechanisms mediated in part by transcriptional effects on apoB, microsomal triglyceride transfer protein, and lipogenic genes and in part by posttranscriptional effects on the LDLR and microsomal triglyceride transfer protein. These findings indicate that targeted PCSK9-based therapies may also be effective in the management of postprandial hypertriglyceridemia.
authors: From the Department of Pharmacology, Dalhousie University, Halifax, NS, and Saint John, NB, Canada (S.R.); Department of Medicine, Section of Cardiovascular Disease Prevention, Vanderbilt University, Nashville, TN (H.T., M.F.L., J.H., I.G., S.F.); Oregon Health and Science University, Portland (H.T., I.G.); and Department of Biostatistics, Faculty of Medicine, University of Toronto and Cancer Care Ontario, Toronto, ON, Canada (P.E.B.). shirya.rashid@Dal.ca.
authors: Shirya
authors: S
authors: Rashid
authors: From the Department of Pharmacology, Dalhousie University, Halifax, NS, and Saint John, NB, Canada (S.R.); Department of Medicine, Section of Cardiovascular Disease Prevention, Vanderbilt University, Nashville, TN (H.T., M.F.L., J.H., I.G., S.F.); Oregon Health and Science University, Portland (H.T., I.G.); and Department of Biostatistics, Faculty of Medicine, University of Toronto and Cancer Care Ontario, Toronto, ON, Canada (P.E.B.).
authors: Hagai
authors: H
authors: Tavori
authors: From the Department of Pharmacology, Dalhousie University, Halifax, NS, and Saint John, NB, Canada (S.R.); Department of Medicine, Section of Cardiovascular Disease Prevention, Vanderbilt University, Nashville, TN (H.T., M.F.L., J.H., I.G., S.F.); Oregon Health and Science University, Portland (H.T., I.G.); and Department of Biostatistics, Faculty of Medicine, University of Toronto and Cancer Care Ontario, Toronto, ON, Canada (P.E.B.).
authors: Patrick E
authors: PE
authors: Brown
authors: From the Department of Pharmacology, Dalhousie University, Halifax, NS, and Saint John, NB, Canada (S.R.); Department of Medicine, Section of Cardiovascular Disease Prevention, Vanderbilt University, Nashville, TN (H.T., M.F.L., J.H., I.G., S.F.); Oregon Health and Science University, Portland (H.T., I.G.); and Department of Biostatistics, Faculty of Medicine, University of Toronto and Cancer Care Ontario, Toronto, ON, Canada (P.E.B.).
authors: MacRae F
authors: MF
authors: Linton
authors: From the Department of Pharmacology, Dalhousie University, Halifax, NS, and Saint John, NB, Canada (S.R.); Department of Medicine, Section of Cardiovascular Disease Prevention, Vanderbilt University, Nashville, TN (H.T., M.F.L., J.H., I.G., S.F.); Oregon Health and Science University, Portland (H.T., I.G.); and Department of Biostatistics, Faculty of Medicine, University of Toronto and Cancer Care Ontario, Toronto, ON, Canada (P.E.B.).
authors: Jane
authors: J
authors: He
authors: From the Department of Pharmacology, Dalhousie University, Halifax, NS, and Saint John, NB, Canada (S.R.); Department of Medicine, Section of Cardiovascular Disease Prevention, Vanderbilt University, Nashville, TN (H.T., M.F.L., J.H., I.G., S.F.); Oregon Health and Science University, Portland (H.T., I.G.); and Department of Biostatistics, Faculty of Medicine, University of Toronto and Cancer Care Ontario, Toronto, ON, Canada (P.E.B.).
authors: Ilaria
authors: I
authors: Giunzioni
authors: From the Department of Pharmacology, Dalhousie University, Halifax, NS, and Saint John, NB, Canada (S.R.); Department of Medicine, Section of Cardiovascular Disease Prevention, Vanderbilt University, Nashville, TN (H.T., M.F.L., J.H., I.G., S.F.); Oregon Health and Science University, Portland (H.T., I.G.); and Department of Biostatistics, Faculty of Medicine, University of Toronto and Cancer Care Ontario, Toronto, ON, Canada (P.E.B.).
authors: Sergio
authors: S
authors: Fazio
mesh_terms: D000818:Animals; D001055:Apolipoproteins B / Q000235:genetics / Q000378:metabolism*; D018938:Caco-2 Cells; D002470:Cell Survival / Q000502:physiology; D020895:Enterocytes / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D015228:Hypertriglyceridemia / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000166:cytology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism*; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000502:physiology; D014280:Triglycerides / Q000378:metabolism*
chemical_list: D001055:Apolipoproteins B; D034741:RNA, Small Interfering; D011973:Receptors, LDL; D014280:Triglycerides; C472125:PCSK9 protein, human; C472126:Pcsk9 protein, mouse; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases
keywords: apolipoproteins; lipids; molecular biology; pathophysiology; receptors, lipoprotein; risk factors