SLC35G1: A Highly Chloride-Sensitive Transporter Crucial for Basolateral Citrate Absorption in the Intestine

Core Concepts

SLC35G1, a member of the solute carrier (SLC) 35 family, plays a key role in the basolateral membrane transport of citrate in the intestinal absorption process.

Abstract

The study investigated the functional characteristics and physiological role of SLC35G1 in intestinal citrate absorption. Key findings: SLC35G1 was found to be capable of transporting citrate, exhibiting saturation kinetics with a Vmax of 1.10 nmol/min/mg protein and a Km of 519 μM. SLC35G1-mediated citrate transport was extensively inhibited by extracellular chloride ions, with an IC50 value of 6.7 mM, suggesting SLC35G1 is a potential citrate exporter. SLC35G1 was highly expressed in the upper small intestine (duodenum and jejunum) and localized to the basolateral membrane of intestinal epithelial cells. Knockdown of SLC35G1 in Caco-2 cells significantly reduced citrate uptake, providing evidence of its involvement in intestinal citrate absorption. SLC35G1 likely cooperates with the apical membrane transporter NaDC1 to facilitate the transcellular transport of citrate across intestinal epithelial cells. The study reveals SLC35G1 as the first identified basolateral membrane transporter responsible for the intestinal absorption of citrate, with a unique chloride-sensitivity characteristic.

Stats

SLC35G1-mediated citrate uptake exhibited a Vmax of 1.10 nmol/min/mg protein and a Km of 519 μM. The IC50 value for chloride inhibition of SLC35G1-mediated citrate uptake was 6.7 ± 1.4 mM. Knockdown of SLC35G1 in Caco-2 cells significantly reduced citrate uptake.

Quotes

"SLC35G1, to our best knowledge, is the first transporter identified to be extremely sensitive to chloride ions among those functioning on the basolateral membrane of intestinal epithelial cells." "These findings pave the way for several follow-up directions related to the molecular basis of the intestinal absorption of various compounds, including nutrients and drugs."

Key Insights Distilled From

SLC35G1: A highly chloride-sensitive transporter responsible for the basolateral membrane transport in intestinal citrate absorption

by Mimura,Y., Y... at www.biorxiv.org 05-02-2024

https://www.biorxiv.org/content/10.1101/2024.04.29.591675v1

Deeper Inquiries

What other transporters or mechanisms might be involved in the basolateral efflux of citrate and other dicarboxylates in the intestine?

In addition to SLC35G1, which has been identified as a key transporter responsible for the basolateral efflux of citrate in the intestine, there are other transporters and mechanisms that might be involved in this process. One potential candidate is the SLC13 family of transporters, particularly NaDC1, which is known to mediate the luminal absorption of citrate in the small intestine. NaDC1 could potentially work in conjunction with SLC35G1 to facilitate the bidirectional transport of citrate across the intestinal epithelial cells. Additionally, other members of the SLC35 family, such as SLC35E, SLC35F, and SLC35G, whose functions are not yet fully elucidated, could also play a role in the basolateral efflux of citrate and other dicarboxylates. Furthermore, organic anion transporters and cation transporters, as well as other carrier-mediated systems, may contribute to the overall transport of citrate and related compounds across the basolateral membrane of intestinal epithelial cells.

How might the chloride-sensitivity of SLC35G1 be leveraged for the targeted delivery or modulation of citrate-related compounds?

The chloride-sensitivity of SLC35G1 presents an intriguing opportunity for the targeted delivery or modulation of citrate-related compounds. By understanding the mechanism through which chloride ions affect the transport activity of SLC35G1, it may be possible to design specific strategies to manipulate this process for therapeutic purposes. For example, the development of chloride-sensitive inhibitors or activators could be explored to regulate the transport of citrate by SLC35G1. This could have implications for conditions where citrate absorption or metabolism is dysregulated, such as in metabolic disorders or certain types of kidney stones. Additionally, leveraging the chloride-sensitivity of SLC35G1 could potentially be used to enhance the bioavailability of citrate-related compounds in pharmaceutical formulations, allowing for targeted delivery to specific tissues or cells where SLC35G1 is highly expressed.

Given the high expression of SLC35G1 in the testis, what other physiological roles might this transporter play beyond intestinal citrate absorption?

The high expression of SLC35G1 in the testis suggests that this transporter may have additional physiological roles beyond intestinal citrate absorption. One potential function of SLC35G1 in the testis could be related to the transport of essential nutrients or metabolites required for spermatogenesis and sperm function. Citrate, being a key intermediate in energy metabolism, may play a role in providing energy for sperm motility and function. Therefore, SLC35G1 could be involved in the uptake or release of citrate in the testis to support these processes. Moreover, SLC35G1 may participate in the transport of other substrates critical for male reproductive health, such as nucleoside-sugars or other bioactive compounds. Further research is needed to elucidate the specific roles of SLC35G1 in the testis and its implications for male fertility and reproductive function.