Menin orchestrates hepatic glucose and fatty acid uptake via deploying the cellular translocation of SIRT1 and PPARγ

Cell & Bioscience

Research

Lili Sun¹  Ranran Li¹  Zhongjin Xu¹  Shengxuan Wang¹  Jingxuan Zhou²  Xuanning Wu²  Tingjun Liu²  Kerong Shi² 

[1]Laboratory of Animal Stem Cell and Reprogramming, College of Animal Science and Technology, Shandong Agricultural University, No. 61 Daizong Street, 271018, Taian, Shandong, People’s Republic of China

[2]Laboratory of Animal Stem Cell and Reprogramming, College of Animal Science and Technology, Shandong Agricultural University, No. 61 Daizong Street, 271018, Taian, Shandong, People’s Republic of China

[3]Key Laboratory of Animal Bioengineering and Disease Prevention of Shandong Province, 271018, Taian, Shandong, People’s Republic of China

关键词: Menin;    Hepatocytes;    PPARγ;    SIRT1;    NAFLD;    Metabolism homeostatsis;   

DOI  :  10.1186/s13578-023-01119-y

 received in 2023-06-05, accepted in 2023-08-30,  发布年份 2023

来源: Springer

【 摘 要 】

BackgroundMenin is a scaffold protein encoded by the Men1 gene, which interacts with various transcriptional proteins to activate or repress cellular processes and is a key mediator in multiple organs. Both liver-specific and hepatocyte-specific Menin deficiency promotes high-fat diet-induced liver steatosis in mice, as well as insulin resistance and type 2 diabetic phenotype. The potential link between Menin and hepatic metabolism homeostasis may provide new insights into the mechanism of fatty liver disease.ResultsDisturbance of hepatic Menin expression impacts metabolic pathways associated with non-alcoholic fatty liver disease (NAFLD), including the FoxO signaling pathway, which is similar to that observed in both oleic acid-induced fatty hepatocytes model and biopsied fatty liver tissues, but with elevated hepatic Menin expression and inhibited FABP1. Higher levels of Menin facilitate glucose uptake while restraining fatty acid uptake. Menin targets the expression of FABP3/4/5 and also CD36 or GK, PCK by binding to their promoter regions, while recruiting and deploying the cellular localization of PPARγ and SIRT1 in the nucleus and cytoplasm. Accordingly, Menin binds to PPARγ and/or FoxO1 in hepatocytes, and orchestrates hepatic glucose and fatty acid uptake by recruiting SIRT1.ConclusionMenin plays an orchestration role as a transcriptional activator and/or repressor to target downstream gene expression levels involved in hepatic energy uptake by interacting with the cellular energy sensor SIRT1, PPARγ, and/or FoxO1 and deploying their translocations between the cytoplasm and nucleus, thereby maintaining metabolic homeostasis. These findings provide more evidence suggesting Menin could be targeted for the treatment of hepatic steatosis, NAFLD or metabolic dysfunction-associated fatty liver disease (MAFLD), and even other hepatic diseases.Graphical Abstract

【 授权许可】

CC BY   
© Society of Chinese Bioscientists in America (SCBA) 2023

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