title: Role of Insulin in the Regulation of Proprotein Convertase Subtilisin/Kexin Type 9.
abstract: OBJECTIVE
  Proprotein convertase subtilisin/kexin type 9 (PCSK9), which binds the low-density lipoprotein receptor and targets it for degradation, has emerged as an important regulator of serum cholesterol levels and cardiovascular disease risk. Although much work is currently focused on developing therapies for inhibiting PCSK9, the endogenous regulation of PCSK9, particularly by insulin, remains unclear. The objective of these studies was to determine the effects of insulin on PCSK9 in vitro and in vivo.
  
  
  RESULTS
  Using rat hepatoma cells and primary rat hepatocytes, we found that insulin increased PCSK9 expression and increased low-density lipoprotein receptor degradation in a PCSK9-dependent manner. In parallel, hepatic Pcsk9 mRNA and plasma PCSK9 protein levels were reduced by 55% to 75% in mice with liver-specific knockout of the insulin receptor; 75% to 88% in mice made insulin-deficient with streptozotocin; and 65% in ob/ob mice treated with antisense oligonucleotides against the insulin receptor. However, antisense oligonucleotide-mediated knockdown of insulin receptor in lean, wild-type mice had little effect. In addition, we found that fasting was able to reduce PCSK9 expression by 80% even in mice that lack hepatic insulin signaling.
  
  
  CONCLUSIONS
  Taken together, these data indicate that although insulin induces PCSK9 expression, it is not the sole or even dominant regulator of PCSK9 under all conditions.
authors.affiliation: From the Division of Endocrinology, Boston Children's Hospital, Harvard Medical School, MA (J.M., P.V.M., M.E.H., A.V.L., D.-J.S., S.B.B.); Cardiovascular Disease Research, Isis Pharmaceuticals, Carlsbad, CA (M.J.G., R.M.C.); and Department of Veterans Affairs, VA Palo Alto Healthcare System, CA (J.L.).
authors.forename: Ji
authors.initials: J
authors.lastname: Miao
authors.affiliation: From the Division of Endocrinology, Boston Children's Hospital, Harvard Medical School, MA (J.M., P.V.M., M.E.H., A.V.L., D.-J.S., S.B.B.); Cardiovascular Disease Research, Isis Pharmaceuticals, Carlsbad, CA (M.J.G., R.M.C.); and Department of Veterans Affairs, VA Palo Alto Healthcare System, CA (J.L.).
authors.forename: Praveen V
authors.initials: PV
authors.lastname: Manthena
authors.affiliation: From the Division of Endocrinology, Boston Children's Hospital, Harvard Medical School, MA (J.M., P.V.M., M.E.H., A.V.L., D.-J.S., S.B.B.); Cardiovascular Disease Research, Isis Pharmaceuticals, Carlsbad, CA (M.J.G., R.M.C.); and Department of Veterans Affairs, VA Palo Alto Healthcare System, CA (J.L.).
authors.forename: Mary E
authors.initials: ME
authors.lastname: Haas
authors.affiliation: From the Division of Endocrinology, Boston Children's Hospital, Harvard Medical School, MA (J.M., P.V.M., M.E.H., A.V.L., D.-J.S., S.B.B.); Cardiovascular Disease Research, Isis Pharmaceuticals, Carlsbad, CA (M.J.G., R.M.C.); and Department of Veterans Affairs, VA Palo Alto Healthcare System, CA (J.L.).
authors.forename: Alisha V
authors.initials: AV
authors.lastname: Ling
authors.affiliation: From the Division of Endocrinology, Boston Children's Hospital, Harvard Medical School, MA (J.M., P.V.M., M.E.H., A.V.L., D.-J.S., S.B.B.); Cardiovascular Disease Research, Isis Pharmaceuticals, Carlsbad, CA (M.J.G., R.M.C.); and Department of Veterans Affairs, VA Palo Alto Healthcare System, CA (J.L.).
authors.forename: Dong-Ju
authors.initials: DJ
authors.lastname: Shin
authors.affiliation: From the Division of Endocrinology, Boston Children's Hospital, Harvard Medical School, MA (J.M., P.V.M., M.E.H., A.V.L., D.-J.S., S.B.B.); Cardiovascular Disease Research, Isis Pharmaceuticals, Carlsbad, CA (M.J.G., R.M.C.); and Department of Veterans Affairs, VA Palo Alto Healthcare System, CA (J.L.).
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Graham
authors.affiliation: From the Division of Endocrinology, Boston Children's Hospital, Harvard Medical School, MA (J.M., P.V.M., M.E.H., A.V.L., D.-J.S., S.B.B.); Cardiovascular Disease Research, Isis Pharmaceuticals, Carlsbad, CA (M.J.G., R.M.C.); and Department of Veterans Affairs, VA Palo Alto Healthcare System, CA (J.L.).
authors.forename: Rosanne M
authors.initials: RM
authors.lastname: Crooke
authors.affiliation: From the Division of Endocrinology, Boston Children's Hospital, Harvard Medical School, MA (J.M., P.V.M., M.E.H., A.V.L., D.-J.S., S.B.B.); Cardiovascular Disease Research, Isis Pharmaceuticals, Carlsbad, CA (M.J.G., R.M.C.); and Department of Veterans Affairs, VA Palo Alto Healthcare System, CA (J.L.).
authors.forename: Jingwen
authors.initials: J
authors.lastname: Liu
authors.affiliation: From the Division of Endocrinology, Boston Children's Hospital, Harvard Medical School, MA (J.M., P.V.M., M.E.H., A.V.L., D.-J.S., S.B.B.); Cardiovascular Disease Research, Isis Pharmaceuticals, Carlsbad, CA (M.J.G., R.M.C.); and Department of Veterans Affairs, VA Palo Alto Healthcare System, CA (J.L.). sudha.biddinger@childrens.harvard.edu.
authors.forename: Sudha B
authors.initials: SB
authors.lastname: Biddinger
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular; D002460:Cell Line; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism; D006207:Half-Life; D022781:Hepatocytes / Q000378:metabolism; D007328:Insulin / Q000494:pharmacology* / Q000502:physiology*; D018345:Mice, Knockout; D008820:Mice, Obese; D000071449:Proprotein Convertase 9; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011973:Receptors, LDL / Q000378:metabolism; D012697:Serine Endopeptidases / Q000187:drug effects / Q000378:metabolism*
chemical_list: D007328:Insulin; D012333:RNA, Messenger; D011973:Receptors, LDL; C510804:PCSK9 protein, rat; D000071449:Proprotein Convertase 9; D012697:Serine Endopeptidases
keywords: LDL receptor; diabetes mellitus; insulin; insulin resistance