Novel mechanism for zinc inducing hepatic lipolysis via the HDAC3-mediated deacetylation of β-catenin at lysine 311

Abstract

Zinc (Zn) is a multipurpose trace element indispensable for vertebrates and possesses essential regulatory roles in lipid metabolism, but the fundamental mechanism remains largely unknown. In the current study, we found that a high-Zn diet significantly increased hepatic Zn content and influenced the expression of Zn transport-relevant genes. Dietary Zn addition facilitated lipolysis, inhibited lipogenesis, and controlled β-catenin signal; Zn also promoted T-cell factor 7-like 2 (TCF7L2) to interact with β-catenin and regulating its transcriptional activity, thereby inducing lipolysis and inhibiting lipogenesis; Zn-induced lipid degradation was mediated by histone deacetylase 3 (HDAC3) which was responsible for β-catenin deacetylation and the regulation of β-catenin signal under the Zn treatment. Mechanistically, Zn promoted lipid degradation via stimulating HDAC3-mediated deacetylation of β-catenin at lysine 311 (K311), which enhanced the interaction between β-catenin and TCF7L2 and then transcriptionally inhibited fatty acid synthase (FAS), 2-acylglycerol O-acyltransferase 2 (MOGAT2), and sterol regulatory element-binding protein 1 (SREBP1) expression, but elevated the mRNA abundance of adipose triglyceride lipase (ATGL), hormone-sensitive lipase a (HSLA) and carnitine palmitoyltransferase 1a1b (CPT1A1B). Overall, our research reveals a novel mechanism into the important roles of HDAC3/β-catenin pathway in Zn promoting lipolysis and inhibiting lipogenesis, and highlights the essential roles of K311 deacetylation in β-catenin actions and lipolytic metabolism, and accordingly provides novel insight into the prevention and treatment of steatosis in the vertebrates.