Saroglitazar, a novel PPAR-α/γ agonist, modulates thyroid hormone homeostasis through hepatic UGT expression in wistar rats.

PPAR agonists are promising therapeutic agents approved for managing dyslipidemia and insulin resistance, and emerging evidence suggests they may also affect thyroid hormone metabolism by modulating hepatic enzymes and transporters. We aimed to determine whether dual PPAR activation via saroglitazar modulates hepatic enzymes involved in thyroid hormone clearance, thereby bridging metabolic regulation with thyroid function. To investigate this possibility, female rats were dosed orally with saroglitazar (3, 10, or 30 mg/kg/day) for 28 days. Serum T4, T3, and TSH levels were measured using high-sensitivity immunoassays, and hepatic UGT isoforms and thyroid gene expression were assessed by qPCR. Saroglitazar modestly increased T4 and slightly reduced T3, while serum TSH remained stable, suggestive of a well-compensated HPT axis under the study conditions. Mechanistically, saroglitazar markedly induced hepatic UGT1A1 and UGT1A6, key enzymes in T4 glucuronidation and triggered compensatory upregulation of thyroid-specific genes (TSH, TPO, thyroglobulin, and the TSH receptor). Histological analysis revealed no adverse changes in the liver, thyroid, or pituitary glands. Overall, our findings indicate that saroglitazar modulates thyroid hormone homeostasis in rodents primarily via PPAR-mediated peripheral metabolism and intrinsic thyroidal compensation without central HPT disruption; these adaptive changes are rodent-specific due to the lack of thyroxine-binding globulin and unlikely to translate to humans.