Sirtuins, which are a highly conserved family of NAD+-dependent deacetylases, have been shown to be involved in a wide range of physiological and pathological processes, including aging, energy responses to low calorie availability and stress resistance, as well as apoptosis and inflammation.

Now, investigators led by the Indian Institute of Science, Bangalore, have demonstrated the direct role of sirtuin-6 (SIRT6), a nuclear sirtuin, in regulating the cardiac fatty acid uptake in cardiomyocytes via the PPAR-gamma transcription factor, independent of its histone deacetylase catalytic activity. The team reported its results in the June 1, 2021, online issue of Cell Reports.

The contractile process of the heart is energy-intensive and cannot be met through just aerobic oxidation of glucose. Fatty acid oxidation contributes significantly to the energy demands of the heart tissue. Both fatty acid oxidation and its uptake are tightly regulated. When the fatty acid uptake exceeds its oxidation rate, lipid accumulation occurs, triggering mitochondrial dysfunction and compromising cardiac function.

Speaking to BioWorld Science, lead investigator Ravi Sundaresan said the present study was a continuation of the group's effort to elucidate histone deacetylase-independent activities of sirtuin. "In the previous study, we had shown that SIRT6 acts as a key regulator of cellular protein synthesis by transcriptionally regulating the mTOR signaling in partnership with the transcription factor Sp1."

Sundaresan is an associate professor in the Department of Molecular and Cell biology, IISc, where his group studies the role of sirtuin isoforms in the regulation of the pathophysiology of heart failure.

He further added that "sirtuins are known to play a key role in cardiac lipid homeostasis. We had earlier found that cardiac SIRT6 levels were reduced in patients with heart failure. Our previous studies have also shown that SIRT6 plays an important role in energy homeostasis in the heart. To test the effects of SIRT6 on lipotoxicity, we analyzed the levels of SIRT6 in the hearts of diabetic mice and our results indicated an inverse correlation between SIRT6 and fatty acid transporters in diabetic mouse hearts."

To evaluate the effect of SIRT6 on fatty acid uptake, Sundaresan's team knocked down SIRT6 in primary cardiomyocytes. While depletion of SIRT6 increased fatty acid uptake, interestingly this observation was not dependent on the deacetylase catalytic subunit of SIRT6. According to Sundaresan, "the catalytically inactive mutants of SIRT6 effectively suppressed fatty acid uptake like wild-type SIRT6. SIRT6 depletion increased lipid accumulation in cardiomyocytes, while its overexpression had the opposite effect."

Since the uptake of fatty acids is regulated by specific transporters in cardiomyocytes, the authors next tested the expression of these fatty acid transporters in both SIRT6 knockdown and heterozygous mice hearts. They found that the expression of PPAR-gamma, a key regulator of fatty acid transporters, also increased. SIRT6 was also found to transcriptionally regulate the expression of several fatty acid transporters through the PPAR-gamma transcription factor.

Sundaresan added that "SIRT6 is known to activate the PPAR-gamma transcription factor, but as there were no marked changes in the mRNA levels of PPAR-gamma in SIRT6 knockdown cardiomyocytes, we believe that PPAR-gamma was, perhaps, regulated at the post-transcriptional level. Treatment with a PPAR-gamma antagonist was able to nullify the increased lipid accumulation in SIRT6-depleted cardiomyocytes and decreased the expression of fatty acid transporters like CD36, CAV1 and FABP3 in these cells."

The study also analyzed the expression of SIRT6 and fatty acid transporters in the left ventricle of human heart failure patients. The analyses showed that SIRT6 levels were significantly downregulated, and the expression of fatty acid transporters was increased in the heart tissue of such patients.

Sundaresan's team was particularly keen to understand how SIRT6 regulated PPAR-gamma. Their modeling studies indicated that SIRT6 physically interacted with the DNA binding domains of PPAR-gamma and modulated PPAR-gamma-mediated transcriptional activation of fatty acid transporters. However, Sundaresan conceded that further studies are required to identify the residues involved in the interaction of SIRT6 and PPAR-gamma.

According to Sundaresan, "the current study highlights a crucial role for SIRT6 in regulating lipid levels in the failing heart through transcriptional control of fatty acid transporters. We think that activation of SIRT6 via calorie restriction or by pharmacological means may be beneficial in reducing cardiac lipotoxicity."

Sundaresan's team wants to understand next the effect of SIRT6 and PPAR-gamma on fatty acid transport and accumulation in a normal heart and its probable role in physiological energy homeostasis.