Regulation of hepatic LDL receptors by mTORC1 and PCSK9 in mice

Ding Ai, Chiyuan Chen, Seongah Han, Anjali Ganda, Andrew J. Murphy, Rebecca Haeusler, Edward Thorp, Domenico Accili, Jay D. Horton, Alan R. Tall

Research output: Contribution to journalArticle

91 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1262-1270
Number of pages9
JournalJournal of Clinical Investigation
Volume122
Issue number4
DOIs
StatePublished - Apr 2 2012

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LDL Receptors
Liver
Sirolimus
LDL Cholesterol
Type 2 Diabetes Mellitus
Proteins
Hepatocyte Nuclear Factor 1
Insulin
VLDL Cholesterol
mechanistic target of rapamycin complex 1
Insulin Receptor
Immunosuppressive Agents
Dyslipidemias
Small Interfering RNA
Atherosclerosis
Transplants

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Ai, D., Chen, C., Han, S., Ganda, A., Murphy, A. J., Haeusler, R., ... Tall, A. R. (2012). Regulation of hepatic LDL receptors by mTORC1 and PCSK9 in mice. Journal of Clinical Investigation, 122(4), 1262-1270. https://doi.org/10.1172/JCI61919

Regulation of hepatic LDL receptors by mTORC1 and PCSK9 in mice. / Ai, Ding; Chen, Chiyuan; Han, Seongah; Ganda, Anjali; Murphy, Andrew J.; Haeusler, Rebecca; Thorp, Edward; Accili, Domenico; Horton, Jay D.; Tall, Alan R.

In: Journal of Clinical Investigation, Vol. 122, No. 4, 02.04.2012, p. 1262-1270.

Research output: Contribution to journalArticle

Ai, D, Chen, C, Han, S, Ganda, A, Murphy, AJ, Haeusler, R, Thorp, E, Accili, D, Horton, JD & Tall, AR 2012, 'Regulation of hepatic LDL receptors by mTORC1 and PCSK9 in mice', Journal of Clinical Investigation, vol. 122, no. 4, pp. 1262-1270. https://doi.org/10.1172/JCI61919
Ai D, Chen C, Han S, Ganda A, Murphy AJ, Haeusler R et al. Regulation of hepatic LDL receptors by mTORC1 and PCSK9 in mice. Journal of Clinical Investigation. 2012 Apr 2;122(4):1262-1270. https://doi.org/10.1172/JCI61919
Ai, Ding ; Chen, Chiyuan ; Han, Seongah ; Ganda, Anjali ; Murphy, Andrew J. ; Haeusler, Rebecca ; Thorp, Edward ; Accili, Domenico ; Horton, Jay D. ; Tall, Alan R. / Regulation of hepatic LDL receptors by mTORC1 and PCSK9 in mice. In: Journal of Clinical Investigation. 2012 ; Vol. 122, No. 4. pp. 1262-1270.
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