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

TY - JOUR

T1 - Novel mechanism for zinc inducing hepatic lipolysis via the HDAC3-mediated deacetylation of β-catenin at lysine 311

AU - Xu, Yi Chuang

AU - Zheng, Hua

AU - Hogstrand, Christer

AU - Tan, Xiao Ying

AU - Zhao, Tao

AU - Song, Yu Feng

AU - Wei, Xiao Lei

AU - Wu, Li Xiang

AU - Luo, Zhi

N1 - Publisher Copyright: © 2023 Elsevier Inc.

PY - 2023/11

Y1 - 2023/11

N2 - 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.

AB - 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.

KW - deacetylation

KW - HDAC3/β-catenin pathway

KW - lipid metabolism

KW - NAFLD

KW - vertebrates

KW - Zinc

UR - http://www.scopus.com/inward/record.url?scp=85169509873&partnerID=8YFLogxK

U2 - 10.1016/j.jnutbio.2023.109429

DO - 10.1016/j.jnutbio.2023.109429

M3 - Article

C2 - 37591442

AN - SCOPUS:85169509873

SN - 0955-2863

VL - 121

JO - JOURNAL OF NUTRITIONAL BIOCHEMISTRY

JF - JOURNAL OF NUTRITIONAL BIOCHEMISTRY

M1 - 109429

ER -