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Mapping the molecular signatures of diet-induced NASH and its regulation by the hepatokine Tsukushi.

Abstract：

OBJECTIVE:Nonalcoholic steatohepatitis (NASH) is closely associated with metabolic syndrome and increases the risk for end-stage liver disease, such as cirrhosis and hepatocellular carcinoma. Despite this, the molecular events that influence NASH pathogenesis remain poorly understood. The objectives of the current study are to delineate the transcriptomic and proteomic signatures of NASH liver, to identify potential pathogenic pathways and factors, and to critically assess their role in NASH pathogenesis. METHODS:We performed RNA sequencing and quantitative proteomic analyses on the livers from healthy and diet-induced NASH mice. We examined the association between plasma levels of TSK, a newly discovered hepatokine, and NASH pathologies and reversal in response to dietary switch in mice. Using TSK knockout mouse model, we determined how TSK deficiency modulates key aspects of NASH pathogenesis. RESULTS:RNA sequencing and quantitative proteomic analyses revealed that diet-induced NASH triggers concordant reprogramming of the liver transcriptome and proteome in mice. NASH pathogenesis is linked to elevated plasma levels of the hepatokine TSK, whereas dietary switch reverses NASH pathologies and reduces circulating TSK concentrations. Finally, TSK inactivation protects mice from diet-induced NASH and liver transcriptome remodeling. CONCLUSIONS:Global transcriptomic and proteomic profiling of healthy and NASH livers revealed the molecular signatures of diet-induced NASH and dysregulation of the liver secretome. Our study illustrates a novel pathogenic mechanism through which elevated TSK in circulation promotes NASH pathologies, thereby revealing a potential target for therapeutic intervention.

journal_name

Mol Metab

journal_title

Molecular metabolism

authors

Xiong X,Wang Q,Wang S,Zhang J,Liu T,Guo L,Yu Y,Lin JD

doi

10.1016/j.molmet.2018.12.004

subject

Has Abstract

pub_date

2019-02-01 00:00:00

pages

128-137

issn

2212-8778

pii

S2212-8778(18)31116-5

journal_volume

20

pub_type

杂志文章

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