Dataset Information

Deficiency of WTAP in hepatocytes induces lipoatrophy and non-alcoholic steatohepatitis (NASH).

ABSTRACT: Ectopic lipid accumulation and inflammation are the essential signs of NASH. However, the molecular mechanisms of ectopic lipid accumulation and inflammation during NASH progression are not fully understood. Here we reported that hepatic Wilms' tumor 1-associating protein (WTAP) is a key integrative regulator of ectopic lipid accumulation and inflammation during NASH progression. Hepatic deletion of Wtap leads to NASH due to the increased lipolysis in white adipose tissue, enhanced hepatic free fatty acids uptake and induced inflammation, all of which are mediated by IGFBP1, CD36 and cytochemokines such as CCL2, respectively. WTAP binds to specific DNA motifs which are enriched in the promoters and suppresses gene expression (e.g., Igfbp1, Cd36 and Ccl2) with the involvement of HDAC1. In NASH, WTAP is tranlocated from nucleus to cytosol, which is related to CDK9-mediated phosphorylation. These data uncover a mechanism by which hepatic WTAP regulates ectopic lipid accumulation and inflammation during NASH progression.

SUBMITTER: Li X

PROVIDER: S-EPMC9352699 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Deficiency of WTAP in hepatocytes induces lipoatrophy and non-alcoholic steatohepatitis (NASH).

Li Xinzhi X Ding Kaixin K Li Xueying X Yuan Bingchuan B Wang Yuqin Y Yao Zhicheng Z Wang Shuaikang S Huang He H Xu Bolin B Xie Liwei L Deng Tuo T Chen Xiao-Wei XW Chen Zheng Z

Nature communications 20220804 1

Ectopic lipid accumulation and inflammation are the essential signs of NASH. However, the molecular mechanisms of ectopic lipid accumulation and inflammation during NASH progression are not fully understood. Here we reported that hepatic Wilms' tumor 1-associating protein (WTAP) is a key integrative regulator of ectopic lipid accumulation and inflammation during NASH progression. Hepatic deletion of Wtap leads to NASH due to the increased lipolysis in white adipose tissue, enhanced hepatic free ...[more]

PMID: 35927268

Similar Datasets

Project description:The mechanisms underlying the progression of non-alcoholic steatohepatitis (NASH) are not completely elucidated. In this study we have integrated gene expression profiling of liver biopsies of NASH patients with translational studies in a mouse model of steatohepatitis and with pharmacological interventions in isolated hepatocytes to identify a novel mechanism implicated in the pathogenesis of NASH. By using high-density oligonucleotide microarray analysis we identified a significant enrichment of known genes involved in the multi-step catalysis of long chain polyunsaturated fatty acids, including delta-5 and 6 desaturases. A combined inhibitor of delta-5 and delta-6 desaturases significantly reduced intracellular lipid accumulation and inflammatory gene expression in isolated hepatocytes. Gas chromatography analysis revealed impaired delta-5 desaturase activity toward the omega-3 pathway in livers from mice with high-fat diet (HFD)-induced NASH. Consistently, restoration of omega-3 index in transgenic fat-1 mice expressing an omega-3 desaturase, which allows the endogenous conversion of omega-6 into omega-3 fatty acids, produced a significant reduction in hepatic insulin resistance, hepatic steatosis, macrophage infiltration and necroinflammatory liver injury, accompanied by attenuated expression of genes involved in inflammation, fatty acid uptake and lipogenesis. These results were comparable to those obtained in a group of mice receiving a HFD supplemented with EPA/DHA. Of interest, hepatocytes from fat-1 mice or supplemented with EPA exhibited synergistic anti-steatotic and anti-inflammatory actions with the delta-5/ delta-6 inhibitor. Conclusion: These findings indicate that both endogenous and exogenous restoration of the hepatic balance between omega-6 and omega-3 fatty acids and/or modulation of desaturase activities exert preventive actions in NASH. The complete database comprised the expression measurements of 18185 genes for liver sample groups: 8 non-alcoholic steatohepatitis (NASH ) and 7 control samples. This dataset is part of the TransQST collection.

Project description:Non-alcoholic fatty liver disease (NAFLD) is a progressive liver disease characterized by dysregulated lipid metabolism and chronic inflammation ultimately resulting in fibrosis. Untreated, NAFLD may progress to non-alcoholic steatohepatitis (NASH), cirrhosis and death. However, currently there are no FDA approved therapies that treat NAFLD/NASH. Thrombospondin-I (TSP-1) is a large glycoprotein in the extracellular matrix that regulates numerous cellular pathways including transforming growth factor beta 1 (TGF-β1) activation, angiogenesis, inflammation and cellular adhesion. Increased expression of TSP-1 has been reported in various liver diseases; however, its role in NAFLD/NASH is not well understood. We first examined TSP-1 modulation in hepatic stellate cell activation, a critical initiating step in hepatic fibrosis. Knockdown or inhibition of TSP-1 attenuated HSC activation measured by alpha smooth muscle actin (α-SMA) and Collagen I expression. To investigate the impact of TSP-1 modulation in context of NAFLD/NASH, we examined the effect of TSP-1 deficiency in the choline deficient L-amino acid defined high fat diet (CDAHFD) model of NASH in mice by assessing total body and liver weight, serum liver enzyme levels, serum lipid levels, liver steatosis, liver fibrosis and liver gene expression in wild type (WT) and TSP-1 null mice. CDAHFD fed mice, regardless of genotype, developed phenotypes of NASH, including significant increase in liver weight and liver enzymes, steatosis and fibrosis. However, in comparison to WT, CDAHFD-fed TSP-1 deficient mice were protected against numerous NASH phenotypes. TSP-1 null mice exhibited a decrease in serum lipid levels, inflammation markers and hepatic fibrosis. RNA-seq based transcriptomic profiles from the liver of CDAHFD fed mice determined that both WT and TSP-1 null mice exhibited similar gene expression signatures following CDAHFD, similar to biophysical and histological assessment comparison. Comparison of transcriptomic profiles based on genotype suggested that peroxisome proliferator activated receptor alpha (PPARα) pathway and amino acid metabolism pathways are differentially expressed in TSP-1 null mice. Activation of PPARα pathway was supported by observed decrease in serum lipid levels. Our findings provide important insights into the role of TSP-1 in context of NAFLD/NASH and TSP-1 may be a target of interest to develop anti-fibrotic therapeutics for NAFLD/NASH.

Dataset Information

Deficiency of WTAP in hepatocytes induces lipoatrophy and non-alcoholic steatohepatitis (NASH).

Publications

Deficiency of WTAP in hepatocytes induces lipoatrophy and non-alcoholic steatohepatitis (NASH).

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets