[HTML][HTML] Mapping the molecular signatures of diet-induced NASH and its regulation by the hepatokine Tsukushi
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 …
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 …
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.
Elsevier