Peroxisome proliferator-activated receptor α mediates enhancement of gene expression of cerebroside sulfotransferase in several murine organs

Abstract

Sulfatides, 3-O-sulfogalactosylceramides, are known to have multifunctional properties. These molecules are distributed in various tissues of mammals, where they are synthesized from galactosylceramides by sulfation at C3 of the galactosyl residue.Although this reaction is specifically catalyzed by cerebroside sulfotransferase (CST), the mechanisms underlying the transcriptional regulation of this enzyme are not understood. With respect to this issue, we previously found potential sequences of peroxisome proliferator-activated receptor (PPAR) response element on upstream regions of the mouse CST gene and presumed the possible regulation by the nuclear receptor PPARα. To confirm this hypothesis, we treated wild-type and Ppara-null mice with the specific PPARα agonist fenofibrate and examined the amounts of sulfatides and CST gene expression in various tissues. Fenofibrate treatment increased sulfatides and CST mRNA levels in the kidney, heart, liver, and small intestine in a PPARα-dependent manner. However, these effects of fenofibrate were absent in the brain or colon.Fenofibrate treatment did not affect the mRNA level of arylsulfatase A, which is the key enzyme for catalyzing desulfation of sulfatides, in any of these six tissues. Analyses of the DNA-binding activity and conventional gene expression targets of PPARα has demonstrated that fenofibrate treatment activated PPARα in the kidney, heart, liver, and 4 small intestine but did not affect the brain or colon. These findings suggest that PPARα activation induces CST gene expression and enhances sulfatide synthesis in mice, which suggests that PPARα is a possible transcriptional regulator for the mouse CST gene.(less than 250 words)

Activation of PPAR<i>α</i> by Fatty Acid Accumulation Enhances Fatty Acid Degradation and Sulfatide Synthesis

“…This PPARα activation enhances expression levels of the two key enzymes in sulfatide synthesis, SPT and CST, and increases sulfatide content without changing the sphingoid composition. The relationship between CST expression and PPARα activation has been identified in human cells in our present study, and previously in mice (Kimura et al 2012;Nakajima et al 2013). However, the relationship between SPT expression and PPARα remains controversial.…”

“…This is because the two possible rate-limiting reactions catalyzed by serine palmitoyl-CoA transferase (SPT) and cerebroside sulfotransferase (CST) in the sulfatide synthesis pathway (Fig. 1) are potently regulated through PPAR in rodents (Rivier et al 2000;Baranowski et al 2007;Zabielski et al 2010;Yamane et al 2011;Kimura et al 2012;Nakajima et al 2013). Our study also investigates the control mechanisms involved in human sulfatide metabolism, which are currently unknown.…”

“…Here, we have focused our attention on sulfatides, which are specific and ubiquitous glycos phingo lipids built from ceramide, galactose, and sulfate ( Fig. 1) (Nakajima et al 2013). This is because the two possible rate-limiting reactions catalyzed by serine palmitoyl-CoA transferase (SPT) and cerebroside sulfotransferase (CST) in the sulfatide synthesis pathway (Fig.…”

Age-dependent PPARα activation induces hepatic sulfatide accumulation in transgenic mice carrying the hepatitis C virus core gene

“…As reported previously [30], age-dependent PPARα activation was also detected in the same HCVcpTg mice. Earlier studies reported that PPARα agonist treatment could increase the mRNA and protein expression levels of SPT and CST by PPARα activation in various cell and animal experiments [17,31]. Furthermore, the current study demonstrated that the PPARα inhibitor MK886 can dramatically reverse the expression levels of SPT and CST.…”

“…However, mechanisms underlying PPARα-mediated carcinogenesis still remain unclear. We recently reported that PPARα also controls sulfatide metabolism in mice [16,17], primarily through transcriptional activation of the gene encoding cerebroside (galactosylceramide) sulfotransferase (CST). CST catalyzes the last reaction in sulfatide synthesis, i.e., 3-O-sulfation of galactosylceramides [18] and is essential for the generation of sulfatide molecules [2].…”