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Transcriptional regulation of OCTN2 is mediated in part by the peroxisome proliferator‐activated receptor α (PPARα). PPARα plays an important role in the regulation of genes involved in lipid metabolism and energy homeostasis and is highly expressed in tissues that use fatty acid oxidation as a primary energy source, including heart muscle, skeletal muscle, and kidney [82]. Notably, OCTN2 is expressed highly in these tissues as well. Tentative PPAR response elements (PPREs) are found in the promoter and intronic regions of SLC22A5 in several species. In rats, treatment with the PPARα agonist clofibrate leads to increased transcription of OCTN2 in the liver and small intestine, but not the kidney or muscle tissue. Aligned with the upregulation of OCTN2 in rat liver, hepatic concentrations of carnitine are also increased by PPARα activation. These findings are supported by the downregulation of OCTN2 and overall reduction in systemic carnitine levels in PPARα‐null mice. Upregulation of OCTN2 by PPARα has also been demonstrated in pigs. In addition to fibrates, PPARα‐mediated regulation of OCTN2 is affected by cisplatin. Cisplatin is hypothesized to inhibit DNA binding to the PPARα/RXR complex, resulting in an overall downregulation of OCTN2 and an increase in urinary carnitine wasting in mice [91]. The PPARγ/RXRα complex also modulates OCTN2 expression in the large intestine. Human colonocytes and mouse colon exhibit altered expression of OCTN2 in response to PPARγ, but not PPARα [92]. In a mouse model of IBD, proinflammatory cytokines interact with the PPARγ/RXRα complex to reduce OCTN2 expression, contributing to disease pathology. Treatment with the PPARγ agonist luteolin to rescue OCTN2 expression results in the reduction of colonic inflammation [93].

OCTN2 is upregulated by the estrogen receptor (ER) in breast cancer cells and tumor tissue, an effect attributed to the identification of a novel estrogen‐responsive element (ERE) in an intronic region of SLC22A5 [2].

OCTN2 is further regulated by PDZ domain‐containing proteins [83]. PDZK1 colocalizes with OCTN2 at the apical membrane of renal tubule cells. PDZK1 stimulates carnitine uptake via OCTN2 by increasing the V _max of the transporter, although cell‐surface expression of OCTN2 is unchanged suggesting PDZK1 stimulates translocation of carnitine. The four terminal amino acids at the carboxyl end of OCTN2 serve as a PDZ binding motif, and deletion or substitution of these residues eliminates PDZK1 stimulation of OCTN2. PDZK2 also increases the transport capacity of OCTN2, but through a different mechanism, increasing localization of OCTN2 to the plasma membrane [83].

Lastly, OCTN2 expression is regulated by heat shock transcription factor 1 (HSF1) [2]. The promoter variant −207G>C disrupts a consensus sequence for an HSF binding element. Cells with the −207G wild‐type promoter containing the intact HSF1 binding site have higher expression of OCTN2 after heat‐shock compared to cells with the −207C variant, which results in disrupted HSF1 binding.