PD548 - STABILIZATION OF INSULIN RECEPTOR MRNA BY STAR-PAP IN METABOLIC HOMEOSTASIS

PD548

STABILIZATION OF INSULIN RECEPTOR MRNA BY STAR-PAP IN METABOLIC HOMEOSTASIS

N. Chen¹, X. Shen^2,*

¹NHC Key Laboratory of Clinical Nutrition and Intervention, ²The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China

Rationale: Poly(A) polymerases (PAPs) have poorly defined metabolic functions. A rare Star-PAP variant (p.D469N) present in lean but absent in obese individuals suggests a potential role in adipose regulation, yet the underlying mechanism is unknown.

Methods: A Star-PAP variant was identified by comparing lean versus obese human cohorts. Adipose-specific Star-PAP knockout (KO) mice were generated and phenotyped for adipose tissue, hepatic steatosis, and insulin resistance. Mechanistically, RNA binding assays, mRNA decay analyses, insulin receptor (InsR) signaling, lipid storage, acetyl-CoA levels, histone acetylation, and pyruvate supplementation were assessed using standard biochemical and statistical methods.

Results: Adipose-specific Star-PAP KO mice exhibited progressive adipose loss, hepatic steatosis, and severe insulin resistance, mimicking human lipodystrophy. Star-PAP directly bound the InsR 3′UTR to stabilize its transcript; KO accelerated InsR mRNA decay, impairing insulin signaling and adipocyte lipid storage. Genetic restoration of InsR in adipocytes rescued the lipodystrophic phenotypes. Star-PAP deficiency disrupted acetyl-CoA homeostasis secondary to insulin signaling defects, reducing histone acetylation at fatty acid synthesis genes. Pyruvate supplementation restored acetyl-CoA levels, histone acetylation, metabolic gene expression, and lipogenesis.

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Conclusion: Star-PAP-mediated RNA polyadenylation is a novel regulator of adipose homeostasis through stabilization of InsR mRNA. This positions Star-PAP as a key factor in insulin signaling and lipodystrophy, with potential therapeutic implications for metabolic diseases.

Disclosure of Interest: None declared