Regulation of the expression of the hepatocellular sulfate–oxalate exchanger SAT-1 (SLC26A1) by glyoxylate: A metabolic link between liver and kidney?

Abstract

See Article, pages 513-520The liver and kidney are the key organs in detoxification of endogenous and exogenous substances from the body. Detoxification of lipophilic endogenous substances and lipophilic xenobiotics involves biotransformation. This process starts with functionalization of the molecule, often by a member of the family of cytochrome P450 enzymes, followed by conjugation with a hydrophilic molecule, e.g. by glucuronidation or sulfonation. In the case of sulfonation, the sulfate donor for sulfotransferases is 3 0 -phosphoadenosine 5 0 -phosphosulfate, which is synthesized from sulfate and ATP [9]. Hence, ongoing sulfonation requires supply of sulfate as inorganic anion. Furthermore, sulfation is an important post-translational modification of proteins. In the body, sulfate transport is mediated by two different types of transporters: secondary active sodium-dependent transporters and sodium-independent sulfate/anion exchangers [17]. The role of sulfate transporters in detoxification is highlighted by the observation that mice with a disrupted gene for the sodiumdependent sulfate transporter NaS1 (Slc13a1) or the sodiumindependent sulfate anion transporter Sat-1 (Slc26a1) display hypersulfaturia, hyposulfatemia and increased sensitivity to acetaminophen induced liver injury [5,14], while the role of sulfate transporters in post-translational protein modification is evidenced by lethal and nonlethal disorders in patients with mutations in sulfate transporters [10,12,20] and an impaired intestinal barrier function in mice with a disrupted gene for NaS1 [4].Sat1 is the founding member of the SLC26A family, was cloned from rat liver [1] and is localized to the basolateral plasma membrane of hepatocytes and kidney proximal tubular cells, respectively [8,19]. It acts as an anion exchanger and transports, in addition to sulfate, also chloride, bicarbonate, and oxalate in an electroneutral manner [1,11]. The oxalate pool is fed by dietary oxalate and as such absorbed to a minor extent in the intestine [6]. More important is endogenous oxalate, which is a metabolic end product, mainly derived from ascorbic acid and glycine [6]. Elimination of oxalate from the body is complex, but seems to occur predominantly via the kidney [15] and to a minor extent by the gut. The role of the gut in oxalate homeostasis gains importance with progression of renal failure [3] and is highlighted by the observation that patients with a short bowel have a considerable risk of developing calcium oxalate renal stones [18]. Urolithiasis is also observed in mice with a disrupted Sat1 gene [5]. Therefore, Sat1 may not only be an important transporter involved in sulfate homeostasis but also plays a critical role in the proper excretion of oxalate from the body. Sat-1, therefore, seems to play a broad role in detoxification. Sulfate homeostasis is predominantly, if not exclusively, regulated via renal elimination [16], which also applies to oxalate [15].It is evident from these physiologic and pathophysiologic aspects that understanding ...

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“…[106][107][108][109] The first member of this family that was identified is SLC26A1 (sulfate anion transporter 1 (SAT-1)). This transporter is expressed in the sinusoidal membrane of rat hepatocytes, 106,107,[109][110][111][112] the basolateral membrane of renal proximal tubules, 106,107,[109][110][111]113 and enterocytes of several mammalians. 114,115 SLC26A1 has been reported to mediate SO 4…”