title: Regulation of hepatic LDL receptors by mTORC1 and PCSK9 in mice.
abstract: Individuals with type 2 diabetes have an increased risk of atherosclerosis. One factor underlying this is dyslipidemia, which in hyperinsulinemic subjects with early type 2 diabetes is typically characterized by increased VLDL secretion but normal LDL cholesterol levels, possibly reflecting enhanced catabolism of LDL via hepatic LDLRs. Recent studies have also suggested that hepatic insulin signaling sustains LDLR levels. We therefore sought to elucidate the mechanisms linking hepatic insulin signaling to regulation of LDLR levels. In WT mice, insulin receptor knockdown by shRNA resulted in decreased hepatic mTORC1 signaling and LDLR protein levels. It also led to increased expression of PCSK9, a known post-transcriptional regulator of LDLR expression. Administration of the mTORC1 inhibitor rapamycin caused increased expression of PCSK9, decreased levels of hepatic LDLR protein, and increased levels of VLDL/LDL cholesterol in WT but not Pcsk9-/- mice. Conversely, mice with increased hepatic mTORC1 activity exhibited decreased expression of PCSK9 and increased levels of hepatic LDLR protein levels. Pcsk9 is regulated by the transcription factor HNF1α, and our further detailed analyses suggest that increased mTORC1 activity leads to activation of PKCδ, reduced activity of HNF4α and HNF1α, decreased PCSK9 expression, and ultimately increased hepatic LDLR protein levels, which result in decreased circulating LDL levels. We therefore suggest that PCSK9 inhibition could be an effective way to reduce the adverse side effect of increased LDL levels that is observed in transplant patients taking rapamycin as immunosuppressive therapy.
authors.affiliation: Department of Medicine, Columbia University, New York, New York 10032, USA. da2424@columbia.edu
authors.forename: Ding
authors.initials: D
authors.lastname: Ai
authors.forename: Chiyuan
authors.initials: C
authors.lastname: Chen
authors.forename: Seongah
authors.initials: S
authors.lastname: Han
authors.forename: Anjali
authors.initials: A
authors.lastname: Ganda
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Murphy
authors.forename: Rebecca
authors.initials: R
authors.lastname: Haeusler
authors.forename: Edward
authors.initials: E
authors.lastname: Thorp
authors.forename: Domenico
authors.initials: D
authors.lastname: Accili
authors.forename: Jay D
authors.initials: JD
authors.lastname: Horton
authors.forename: Alan R
authors.initials: AR
authors.lastname: Tall
mesh_terms: D000818:Animals; D005786:Gene Expression Regulation / Q000187:drug effects; D051538:Hepatocyte Nuclear Factor 1-alpha / Q000502:physiology; D051557:Hepatocyte Nuclear Factor 4 / Q000502:physiology; D006946:Hyperinsulinism / Q000235:genetics / Q000378:metabolism; D007328:Insulin / Q000502:physiology*; D007333:Insulin Resistance / Q000502:physiology*; D008099:Liver / Q000378:metabolism*; D016031:Liver Transplantation; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008820:Mice, Obese; D046912:Multiprotein Complexes; D011183:Postoperative Complications; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D011506:Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000494:pharmacology; D011972:Receptor, Insulin / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D011973:Receptors, LDL / Q000096:biosynthesis* / Q000235:genetics; D012697:Serine Endopeptidases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases
chemical_list: D051538:Hepatocyte Nuclear Factor 1-alpha; D051557:Hepatocyte Nuclear Factor 4; C496488:Hnf1a protein, mouse; C496593:Hnf4a protein, mouse; D007328:Insulin; D046912:Multiprotein Complexes; D011506:Proteins; D034741:RNA, Small Interfering; D011973:Receptors, LDL; D011972:Receptor, Insulin; C514862:Akt1 protein, mouse; D000076222:Mechanistic Target of Rapamycin Complex 1; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; C472126:Pcsk9 protein, mouse; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases; D020123:Sirolimus