SIRT6 transcriptionally regulates fatty acid transport by suppressing PPARγ

Danish Khan; Tarannum Ara; Venkatraman Ravi; Raksha Rajagopal; Himani Tandon; Jayadevan Parvathy; Edward A. Gonzalez; Ninitha Asirvatham-Jeyaraj; Swati Krishna; Sneha Mishra; Sukanya Raghu; Arvind Singh Bhati; Ankit Kumar Tamta; Subhajit Dasgupta; Ullas Kolthur-Seetharam; Jean Pierre Etchegaray; Raul Mostoslavsky; Prasanna Simha Mohan Rao; Narayanaswamy Srinivasan; Nagalingam Ravi Sundaresan

doi:10.1016/j.celrep.2021.109190

SIRT6 transcriptionally regulates fatty acid transport by suppressing PPARγ

Danish Khan, Tarannum Ara, Venkatraman Ravi, Raksha Rajagopal, Himani Tandon, Jayadevan Parvathy, Edward A. Gonzalez, Ninitha Asirvatham-Jeyaraj, Swati Krishna, Sneha Mishra, Sukanya Raghu, Arvind Singh Bhati, Ankit Kumar Tamta, Subhajit Dasgupta, Ullas Kolthur-Seetharam, Jean Pierre Etchegaray, Raul Mostoslavsky, Prasanna Simha Mohan Rao, Narayanaswamy Srinivasan, Nagalingam Ravi Sundaresan

Rutgers Newark, Biological Sciences

Research output: Contribution to journal › Article › peer-review

34 Scopus citations

Abstract

Pathological lipid accumulation is often associated with enhanced uptake of free fatty acids via specific transporters in cardiomyocytes. Here, we identify SIRT6 as a critical transcriptional regulator of fatty acid transporters in cardiomyocytes. We find that SIRT6 deficiency enhances the expression of fatty acid transporters, leading to enhanced fatty acid uptake and lipid accumulation. Interestingly, the haploinsufficiency of SIRT6 is sufficient to induce the expression of fatty acid transporters and cause lipid accumulation in murine hearts. Mechanistically, SIRT6 depletion enhances the occupancy of the transcription factor PPARγ on the promoters of critical fatty acid transporters without modulating the acetylation of histone 3 at Lys 9 and Lys 56. Notably, the binding of SIRT6 to the DNA-binding domain of PPARγ is critical for regulating the expression of fatty acid transporters in cardiomyocytes. Our data suggest exploiting SIRT6 as a potential therapeutic target for protecting the heart from metabolic diseases.

Original language	English (US)
Article number	109190
Journal	Cell Reports
Volume	35
Issue number	9
DOIs	https://doi.org/10.1016/j.celrep.2021.109190
State	Published - Jun 1 2021

All Science Journal Classification (ASJC) codes

General Biochemistry, Genetics and Molecular Biology

Keywords

PPARγ
SIRT6
cardiomyocytes
fatty acid uptake
heart failure
lipotoxicity

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10.1016/j.celrep.2021.109190

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Khan, D., Ara, T., Ravi, V., Rajagopal, R., Tandon, H., Parvathy, J., Gonzalez, E. A., Asirvatham-Jeyaraj, N., Krishna, S., Mishra, S., Raghu, S., Bhati, A. S., Tamta, A. K., Dasgupta, S., Kolthur-Seetharam, U., Etchegaray, J. P., Mostoslavsky, R., Rao, P. S. M., Srinivasan, N., & Sundaresan, N. R. (2021). SIRT6 transcriptionally regulates fatty acid transport by suppressing PPARγ. Cell Reports, 35(9), Article 109190. https://doi.org/10.1016/j.celrep.2021.109190

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title = "SIRT6 transcriptionally regulates fatty acid transport by suppressing PPARγ",

abstract = "Pathological lipid accumulation is often associated with enhanced uptake of free fatty acids via specific transporters in cardiomyocytes. Here, we identify SIRT6 as a critical transcriptional regulator of fatty acid transporters in cardiomyocytes. We find that SIRT6 deficiency enhances the expression of fatty acid transporters, leading to enhanced fatty acid uptake and lipid accumulation. Interestingly, the haploinsufficiency of SIRT6 is sufficient to induce the expression of fatty acid transporters and cause lipid accumulation in murine hearts. Mechanistically, SIRT6 depletion enhances the occupancy of the transcription factor PPARγ on the promoters of critical fatty acid transporters without modulating the acetylation of histone 3 at Lys 9 and Lys 56. Notably, the binding of SIRT6 to the DNA-binding domain of PPARγ is critical for regulating the expression of fatty acid transporters in cardiomyocytes. Our data suggest exploiting SIRT6 as a potential therapeutic target for protecting the heart from metabolic diseases.",

keywords = "PPARγ, SIRT6, cardiomyocytes, fatty acid uptake, heart failure, lipotoxicity",

author = "Danish Khan and Tarannum Ara and Venkatraman Ravi and Raksha Rajagopal and Himani Tandon and Jayadevan Parvathy and Gonzalez, {Edward A.} and Ninitha Asirvatham-Jeyaraj and Swati Krishna and Sneha Mishra and Sukanya Raghu and Bhati, {Arvind Singh} and Tamta, {Ankit Kumar} and Subhajit Dasgupta and Ullas Kolthur-Seetharam and Etchegaray, {Jean Pierre} and Raul Mostoslavsky and Rao, {Prasanna Simha Mohan} and Narayanaswamy Srinivasan and Sundaresan, {Nagalingam Ravi}",

note = "Publisher Copyright: {\textcopyright} 2021 The Authors",

year = "2021",

month = jun,

day = "1",

doi = "10.1016/j.celrep.2021.109190",

language = "English (US)",

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Khan, D, Ara, T, Ravi, V, Rajagopal, R, Tandon, H, Parvathy, J, Gonzalez, EA, Asirvatham-Jeyaraj, N, Krishna, S, Mishra, S, Raghu, S, Bhati, AS, Tamta, AK, Dasgupta, S, Kolthur-Seetharam, U, Etchegaray, JP, Mostoslavsky, R, Rao, PSM, Srinivasan, N & Sundaresan, NR 2021, 'SIRT6 transcriptionally regulates fatty acid transport by suppressing PPARγ', Cell Reports, vol. 35, no. 9, 109190. https://doi.org/10.1016/j.celrep.2021.109190

TY - JOUR

T1 - SIRT6 transcriptionally regulates fatty acid transport by suppressing PPARγ

AU - Khan, Danish

AU - Ara, Tarannum

AU - Ravi, Venkatraman

AU - Rajagopal, Raksha

AU - Tandon, Himani

AU - Parvathy, Jayadevan

AU - Gonzalez, Edward A.

AU - Asirvatham-Jeyaraj, Ninitha

AU - Krishna, Swati

AU - Mishra, Sneha

AU - Raghu, Sukanya

AU - Bhati, Arvind Singh

AU - Tamta, Ankit Kumar

AU - Dasgupta, Subhajit

AU - Kolthur-Seetharam, Ullas

AU - Etchegaray, Jean Pierre

AU - Mostoslavsky, Raul

AU - Rao, Prasanna Simha Mohan

AU - Srinivasan, Narayanaswamy

AU - Sundaresan, Nagalingam Ravi

PY - 2021/6/1

Y1 - 2021/6/1

N2 - Pathological lipid accumulation is often associated with enhanced uptake of free fatty acids via specific transporters in cardiomyocytes. Here, we identify SIRT6 as a critical transcriptional regulator of fatty acid transporters in cardiomyocytes. We find that SIRT6 deficiency enhances the expression of fatty acid transporters, leading to enhanced fatty acid uptake and lipid accumulation. Interestingly, the haploinsufficiency of SIRT6 is sufficient to induce the expression of fatty acid transporters and cause lipid accumulation in murine hearts. Mechanistically, SIRT6 depletion enhances the occupancy of the transcription factor PPARγ on the promoters of critical fatty acid transporters without modulating the acetylation of histone 3 at Lys 9 and Lys 56. Notably, the binding of SIRT6 to the DNA-binding domain of PPARγ is critical for regulating the expression of fatty acid transporters in cardiomyocytes. Our data suggest exploiting SIRT6 as a potential therapeutic target for protecting the heart from metabolic diseases.

AB - Pathological lipid accumulation is often associated with enhanced uptake of free fatty acids via specific transporters in cardiomyocytes. Here, we identify SIRT6 as a critical transcriptional regulator of fatty acid transporters in cardiomyocytes. We find that SIRT6 deficiency enhances the expression of fatty acid transporters, leading to enhanced fatty acid uptake and lipid accumulation. Interestingly, the haploinsufficiency of SIRT6 is sufficient to induce the expression of fatty acid transporters and cause lipid accumulation in murine hearts. Mechanistically, SIRT6 depletion enhances the occupancy of the transcription factor PPARγ on the promoters of critical fatty acid transporters without modulating the acetylation of histone 3 at Lys 9 and Lys 56. Notably, the binding of SIRT6 to the DNA-binding domain of PPARγ is critical for regulating the expression of fatty acid transporters in cardiomyocytes. Our data suggest exploiting SIRT6 as a potential therapeutic target for protecting the heart from metabolic diseases.

KW - PPARγ

KW - SIRT6

KW - cardiomyocytes

KW - fatty acid uptake

KW - heart failure

KW - lipotoxicity

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U2 - 10.1016/j.celrep.2021.109190

DO - 10.1016/j.celrep.2021.109190

M3 - Article

C2 - 34077730

AN - SCOPUS:85108058060

SN - 2211-1247

VL - 35

JO - Cell Reports

JF - Cell Reports

IS - 9

M1 - 109190

ER -

SIRT6 transcriptionally regulates fatty acid transport by suppressing PPARγ

Abstract

All Science Journal Classification (ASJC) codes

Keywords

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