What is it about?
The molecular mechanism of stress-induced hepatic steatosis is not well known. Human leucine zipper protein (LZIP) regulates the expression of genes involved in inflammation, cell migration, and stress response. The aim of this study was to determine the regulatory role of LZIP in stress-induced hepatic steatosis. We used a microarray analysis to identify LZIP-induced genes involved in hepatic lipid metabolism. LZIP increased the expression of apolipoprotein A-IV (APOA4) mRNA. In the presence of stress inducer, APOA4 promoter analysis was performed, and LZIP-induced lipid accumulation was monitored in mouse primary cells and human tissues. Under Golgi stress conditions, LZIP underwent proteolytic cleavage and was phosphorylated by AKT to protect against proteasome degradation. The stabilized N-terminal LZIP was translocated to the nucleus, where it directly bound to the APOA4 promoter, leading to APOA4 induction. LZIP-induced APOA4 expression resulted in increased absorption of surrounding free fatty acids. LZIP also promoted hepatic steatosis in mouse liver. Both LZIP and APOA4 were highly expressed in human steatosis samples.Our findings indicate that LZIP is anovel modulator of APOA4 expression and hepatic lipid metabolism. LZIP might be a therapeutic target for developing treatment strategies for hepatic steatosis and related metabolic diseases
Why is it important?
our results suggest a novel function of human LZIP in the liver. Under Golgi stress conditions, the cleaved form of LZIP can directly bind to the proximal region of the APOA4 promoter, leading to induction of APOA4 expression. Among genes involved in lipid synthesis and transport, APOA4 was the only gene that was increased by LZIP. LZIP also increased the accumulation of hepatic TGs. Therefore, LZIP might be a novel regulator of hepatic lipid homeostasis via regulating APOA4 expression
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Human leucine zipper protein promotes hepatic steatosis
induction of apolipoprotein A-IV
, The FASEB Journal, February 2017, Federation of American Societies For Experimental Biology (FASEB), DOI: 10.1096/fj.201601227r.
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