Human leucine zipper protein promotes hepatic steatosisviainduction of apolipoprotein A‐IV

Abstract

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 a novel 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.-Kang, M., Kim, J., An, H.-T., Ko, J. Human leucine zipper protein promotes hepatic steatosis induction of apolipoprotein A-IV.

Identification of chromatin‐accessible domains in non‐alcoholic steatohepatitis‐derived hepatocellular carcinoma

“…In agreement with this, we identified several cancer‐related over‐expressed genes, including Cscbp2 , Apoa4 , Anxa2 , Serpine1 , Igfbp1 , and Tubb2a , that were associated with chromatin‐accessible regions in NASH‐derived HCC. It has been reported that up‐regulation of these genes may have significance in the hepatocarcinogenic process, in general, and in the pathogenesis of NAFLD and NAFLD‐associated liver carcinogenesis, in particular …”

“…Apoa4 is a critical gene involved in the regulation of multiple metabolic pathways, including lipid absorption, lipid metabolism, and glucose homeostasis . Emerging evidence suggests a critical role of apolipoproteins, including APOA4, in the pathogenesis of NAFLD Specifically, Kang et al demonstrated that over‐expression of APOA4 promotes lipid accumulation in the liver, and Qin et al reported that the level of APOA4 protein was increased in the genetically obese ( ob/ob ) mice. Furthermore, a marked upregulation of APOA4, as well as SERPINE1 and IGFBP1, has been demonstrated in patients with NAFLD.…”

“…It has been reported that up-regulation of these genes may have significance in the hepatocarcinogenic process, in general, [39][40][41][42][43][44] and in the pathogenesis of NAFLD and NAFLD-associated liver carcinogenesis, in particular. [45][46][47][48][49] Apoa4 is a critical gene involved in the regulation of multiple metabolic pathways, including lipid absorption, lipid metabolism, and glucose homeostasis. 47 protein was increased in the genetically obese (ob/ob) mice.…”

“…[45][46][47][48][49] Apoa4 is a critical gene involved in the regulation of multiple metabolic pathways, including lipid absorption, lipid metabolism, and glucose homeostasis. 47 protein was increased in the genetically obese (ob/ob) mice. Furthermore, a marked upregulation of APOA4, 47,50 as well as SERPINE1 45 and IGFBP1, 48 has been demonstrated in patients with NAFLD.…”

“…47 protein was increased in the genetically obese (ob/ob) mice. Furthermore, a marked upregulation of APOA4, 47,50 as well as SERPINE1 45 and IGFBP1, 48 has been demonstrated in patients with NAFLD.…”