Small proline-rich protein 1A is a novel target of peroxisome proliferator-activated receptor gamma in steatotic liver disease.

Abstract

Peroxisome proliferator-activated receptor gamma (PPARγ) is a central regulator of lipid homeostasis; however, the specific downstream effectors mediating hepatic steatosis remain incompletely defined. In this study, we investigated the molecular basis, by which PPARγ regulates the expression of small proline-rich protein 1 A (SPRR1A) during the development of fatty liver. We initially performed a bioinformatic re-analysis of publicly available microarray datasets to characterize the gene expression profiles associated with hepatic steatosis in leptin-deficient type 2 diabetic (ob/ob) mice and patients with metabolic dysfunction-associated steatotic liver disease (MASLD). SPRR1A expression was markedly elevated in steatotic livers of both human patients and mouse models. This induction was substantially attenuated in ob/ob mice lacking hepatic Pparg, indicating a PPARγ-dependent regulatory mechanism. Consistently, increased hepatic Sprr1a expression was observed in several experimental models of fatty liver disease, including genetic (db/db), dietary (high-fat and Western diets), and alcohol-induced models. In silico transcriptomic analyses of publicly archived human liver samples further demonstrated significantly higher SPRR1A expression in patients with fatty liver disorders, including MASLD, than in non-steatotic controls. Reporter gene and electrophoretic mobility shift analyses demonstrated that PPARγ directly activated Sprr1a transcription through a conserved PPARγ-responsive element in its promoter. Collectively, these results identify Sprr1a as a previously unrecognized transcriptional target of PPARγ in the context of hepatic steatosis.