Ji Miao1, Praveen V Manthena1, Mary E Haas1, Alisha V Ling1, Dong-Ju Shin1, Mark J Graham1, Rosanne M Crooke1, Jingwen Liu1, Sudha B Biddinger2. 1. 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.). 2. 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.
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. APPROACH AND 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.
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. APPROACH AND 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: Joel T Haas; Ji Miao; Dipanjan Chanda; Yanning Wang; Enpeng Zhao; Mary E Haas; Matthew Hirschey; B Vaitheesvaran; Robert V Farese; Irwin J Kurland; Mark Graham; Rosanne Crooke; Fabienne Foufelle; Sudha B Biddinger Journal: Cell Metab Date: 2012-06-06 Impact factor: 27.287
Authors: Sudha B Biddinger; Antonio Hernandez-Ono; Christian Rask-Madsen; Joel T Haas; José O Alemán; Ryo Suzuki; Erez F Scapa; Chhavi Agarwal; Martin C Carey; Gregory Stephanopoulos; David E Cohen; George L King; Henry N Ginsberg; C Ronald Kahn Journal: Cell Metab Date: 2008-02 Impact factor: 27.287
Authors: Ji Miao; Alisha V Ling; Praveen V Manthena; Mary E Gearing; Mark J Graham; Rosanne M Crooke; Kevin J Croce; Ryan M Esquejo; Clary B Clish; David Vicent; Sudha B Biddinger Journal: Nat Commun Date: 2015-04-07 Impact factor: 14.919
Authors: Amy E Levenson; Amy S Shah; Philip R Khoury; Thomas R Kimball; Elaine M Urbina; Sarah D de Ferranti; David M Maahs; Lawrence M Dolan; R Paul Wadwa; Sudha B Biddinger Journal: Pediatr Diabetes Date: 2017-01-17 Impact factor: 4.866
Authors: A E Levenson; C E Milliren; S B Biddinger; C B Ebbeling; H A Feldman; D S Ludwig; S D de Ferranti Journal: Nutr Metab Cardiovasc Dis Date: 2017-01-03 Impact factor: 4.222