Direct regulation of myocardial triglyceride metabolism by the cardiomyocyte circadian clock

Ju Yun Tsai, Petra C. Kienesberger, Thomas Pulinilkunnil, Mary H. Sailors, David J. Durgan, Carolina Villegas-Montoya, Anil Jahoor, Raquel Gonzalez, Merissa E. Garvey, Brandon Boland, Zachary Blasier, Tracy A. McElfresh, Vijayalakshmi Nannegari, Chi Wing Chow, William C. Heird, Margaret P. Chandler, Jason R B Dyck, Molly S. Bray, Martin E. Young

Research output: Contribution to journalArticle

57 Citations (Scopus)

Abstract

Maintenance of circadian alignment between an organism and its environment is essential to ensure metabolic homeostasis. Synchrony is achieved by cell autonomous circadian clocks. Despite a growing appreciation of the integral relation between clocks and metabolism, little is known regarding the direct influence of a peripheral clock on cellular responses to fatty acids. To address this important issue, we utilized a genetic model of disrupted clock function specifically in cardiomyocytes in vivo (termed cardiomyocyte clock mutant (CCM)). CCM mice exhibited altered myocardial response to chronic high fat feeding at the levels of the transcriptome and lipidome as well as metabolic fluxes, providing evidence that the cardiomyocyte clock regulates myocardial triglyceride metabolism. Time-of-day-dependent oscillations in myocardial triglyceride levels, net triglyceride synthesis, and lipolysis were markedly attenuated in CCM hearts. Analysis of key proteins influencing triglyceride turnover suggest that the cardiomyocyte clock inactivates hormone-sensitive lipase during the active/awake phase both at transcriptional and post-translational (via AMP-activated protein kinase) levels. Consistent with increased net triglyceride synthesis during the end of the active/awake phase, high fat feeding at this time resulted in marked cardiac steatosis. These data provide evidence for direct regulation of triglyceride turnover by a peripheral clock and reveal a potential mechanistic explanation for accelerated metabolic pathologies after prevalent circadian misalignment in Western society.

Original languageEnglish (US)
Pages (from-to)2918-2929
Number of pages12
JournalJournal of Biological Chemistry
Volume285
Issue number5
DOIs
StatePublished - Jan 29 2010

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Circadian Clocks
Cardiac Myocytes
Metabolism
Clocks
Triglycerides
Fats
Sterol Esterase
AMP-Activated Protein Kinases
Lipolysis
Genetic Models
Transcriptome
Homeostasis
Fatty Acids
Maintenance
Pathology
Fluxes
Proteins

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology
  • Medicine(all)

Cite this

Tsai, J. Y., Kienesberger, P. C., Pulinilkunnil, T., Sailors, M. H., Durgan, D. J., Villegas-Montoya, C., ... Young, M. E. (2010). Direct regulation of myocardial triglyceride metabolism by the cardiomyocyte circadian clock. Journal of Biological Chemistry, 285(5), 2918-2929. https://doi.org/10.1074/jbc.M109.077800

Direct regulation of myocardial triglyceride metabolism by the cardiomyocyte circadian clock. / Tsai, Ju Yun; Kienesberger, Petra C.; Pulinilkunnil, Thomas; Sailors, Mary H.; Durgan, David J.; Villegas-Montoya, Carolina; Jahoor, Anil; Gonzalez, Raquel; Garvey, Merissa E.; Boland, Brandon; Blasier, Zachary; McElfresh, Tracy A.; Nannegari, Vijayalakshmi; Chow, Chi Wing; Heird, William C.; Chandler, Margaret P.; Dyck, Jason R B; Bray, Molly S.; Young, Martin E.

In: Journal of Biological Chemistry, Vol. 285, No. 5, 29.01.2010, p. 2918-2929.

Research output: Contribution to journalArticle

Tsai, JY, Kienesberger, PC, Pulinilkunnil, T, Sailors, MH, Durgan, DJ, Villegas-Montoya, C, Jahoor, A, Gonzalez, R, Garvey, ME, Boland, B, Blasier, Z, McElfresh, TA, Nannegari, V, Chow, CW, Heird, WC, Chandler, MP, Dyck, JRB, Bray, MS & Young, ME 2010, 'Direct regulation of myocardial triglyceride metabolism by the cardiomyocyte circadian clock', Journal of Biological Chemistry, vol. 285, no. 5, pp. 2918-2929. https://doi.org/10.1074/jbc.M109.077800
Tsai JY, Kienesberger PC, Pulinilkunnil T, Sailors MH, Durgan DJ, Villegas-Montoya C et al. Direct regulation of myocardial triglyceride metabolism by the cardiomyocyte circadian clock. Journal of Biological Chemistry. 2010 Jan 29;285(5):2918-2929. https://doi.org/10.1074/jbc.M109.077800
Tsai, Ju Yun ; Kienesberger, Petra C. ; Pulinilkunnil, Thomas ; Sailors, Mary H. ; Durgan, David J. ; Villegas-Montoya, Carolina ; Jahoor, Anil ; Gonzalez, Raquel ; Garvey, Merissa E. ; Boland, Brandon ; Blasier, Zachary ; McElfresh, Tracy A. ; Nannegari, Vijayalakshmi ; Chow, Chi Wing ; Heird, William C. ; Chandler, Margaret P. ; Dyck, Jason R B ; Bray, Molly S. ; Young, Martin E. / Direct regulation of myocardial triglyceride metabolism by the cardiomyocyte circadian clock. In: Journal of Biological Chemistry. 2010 ; Vol. 285, No. 5. pp. 2918-2929.
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