Abstract
Taurine deficiency has been suggested to contribute to the pathogenesis and complications of advanced hepatic diseases. The molecular basis for a low level of taurine associated with hepatic failure is largely unknown. Using carbon tetrachloride (CCl4)-induced cirrhotic rat model, we found that the activity and expression of cysteine dioxygenase (CDO), a rate-limiting enzyme in taurine synthesis, were significantly decreased in the liver of these rats. To investigate the underlying mechanisms for the suppression, we examined the effects of pathological cytokines on CDO expression in human hepatoma HepG2 cells. Among the several cytokines, transforming growth factor-β (TGF-β), one of the key mediators of fibrogenesis, suppressed Cdo1 gene transcription through the MEK/ERK pathway. Finally, we further examined potential effects of branched-chain amino acids (BCAA) on CDO expression, as it has been reported that oral BCAA supplementation increased plasma taurine level in the patients with liver cirrhosis. BCAA, especially leucine, promoted Cdo1 gene transcription, and attenuated TGF-β-mediated suppression of Cdo1 gene expression. These results indicate that the low plasma level of taurine in advanced hepatic disease is due to decreased hepatic CDO expression, which can be partly attributed to suppressive effect of TGF-β on Cdo1 gene transcription. Furthermore, our observation that BCAA promotes Cdo1 expression suggests that BCAA may be therapeutically useful to improve hepatic taurine metabolism and further suppress dysfunctions associated with low level of taurine in hepatic diseases.Electronic supplementary materialThe online version of this article (doi:10.1007/s00726-014-1693-3) contains supplementary material, which is available to authorized users.
Highlights
Taurine, 2-aminoethanesulfonic acid, is an end product of sulfur containing amino acids (SAA) metabolism with various physiological roles including conjugation with bile acids, stabilization of the cellular plasma membrane, antioxidant effects, osmoregulation, detoxification, and neuroprotective effects (Huxtable 1992; Wu et al 2005)
We first investigated the mRNA expression of the genes involved in taurine metabolism in the kidney and liver. mRNA levels of taurine biosynthetic enzymes such as cysteine dioxygenase (CDO) and cysteine sulfinic acid decarboxylase (CSAD) were significantly decreased in the kidney (Fig. 1a) and the liver (Fig. 1b) of cirrhotic rats
In a previous study exploring the relationship between plasma amino acid profiles and liver fibrosis, it is clearly demonstrated that abnormal SAA
Summary
2-aminoethanesulfonic acid, is an end product of sulfur containing amino acids (SAA) metabolism with various physiological roles including conjugation with bile acids, stabilization of the cellular plasma membrane, antioxidant effects, osmoregulation, detoxification, and neuroprotective effects (Huxtable 1992; Wu et al 2005). Decreased level of taurine in liver failure is suggested to be contributing to the development of liver failure. Taurine transporter knockout mice which exhibit significantly low levels of taurine in plasma and tissues develop chronic hepatitis and liver fibrosis (Warskulat et al 2006). Taurine supplementation to CCl4-induced hepatic fibrotic model rats prevents fibrosis by reducing oxidative stress (Miyazaki et al 2005). A decreased plasma taurine level in cirrhosis is proposed to be related to occurrence of muscle cramps (Yamamoto 1994, 1996; Yamamoto et al 1994; Miyazaki et al 2004), and the taurine supplementation reduced the frequency of muscle cramps (Matsuzaki et al 1993; Yamamoto 1994, 1996; Yamamoto et al 1994). Despite that the several evidences suggest a pathophysiological relationship between taurine deficiency and hepatic failure and its associated complications, the underlying mechanisms for this phenomenon remain to be known
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