Sirtuin 3-mediated pyruvate dehydrogenase activity determines brown adipocytes phenotype under high-salt conditions

Abstract

Previous study indicated that Sirtuin 3 (SIRT3) is a central regulator of adaptive thermogenesis in brown adipose tissue (BAT). Here we investigate the role of SIRT3 in the modulation of cellular phenotype in BAT under high salt intake (HS). HS downregulated SIRT3 level in BAT, accompanied by decreased oxygen consumption rate, and caused a severe loss of BAT characteristics. Mechanically, SIRT3 interacted with pyruvate dehydrogenase E1α (PDHA1) and deacetylated Lys-83 both in vitro and in vivo under HS. In parallel, HS suppressed salt-induced kinase (Sik) 2 phosphorylation. Silencing Sik2 further diminished SIRT3 activity and enhanced acetylation of PDHA1 K83 level. Reconstruction of SIRT3 restored PDH activity and thermogenic markers expression in differentiated brown adipocytes from SIRT3 knockout (KO) mice. In addition, loss of SIRT3 induced selective remodelling of phospholipids and glycerolipids in BAT exposure to HS. These data indicate that SIRT3 is an essential enzymatic switch that controls brown adipose cell phenotype.

Mitochondrial Proteome of Affected Glutamatergic Neurons in a Mouse Model of Leigh Syndrome

“…More specifically, it has been described that acetylation of PDHA1 at K321 reduce the activity of the enzyme. Noteworthy, K321 residue is a SIRT3 substrate (Fan et al, 2014;Wei et al, 2019), and SIRT3-mediated deacetylation of PDHA1 K321 increases PDH activity (Ozden et al, 2014), therefore evidencing that modifications in the acetylation status of this sole residue can direct the activity of the PDH complex. As suggested by our data, reduced PDH activity may be contributing to the Warburg effect by enhancing glycolysis over mitochondrial oxidation of pyruvate (Warburg, 1956;Kroemer and Pouyssegur, 2008;Vander Heiden et al, 2009).…”

Sirtuins: Key players in obesity-associated adipose tissue remodeling

“…SIRT3 deletion aggravates brown-to-white adipocyte conversion induced by high salt via inhibiting mitochondrial biogenesis and perilipin-1 expression; however, restoring SIRT3 prevents high salt-induced brown AT to white AT conversion by improving mitochondrial respiration ( 62 ). Consistently, knockout of SIRT3 promotes the accumulation of lipid droplets in brown AT and blocks the inhibitory effect of capsaicin on HFD-induced brown AT whitening ( 21 ).…”

The potent roles of salt-inducible kinases (SIKs) in metabolic homeostasis and tumorigenesis

“… 2 As a result, sodium intake-induced calcium influx affected by Na + /Ca 2+ exchange system (NCE1), could cause CaMK-mediated SIK1 phosphorylation and activation, 26 , 34 , 35 which was argued by another study. 36 …”