we identified a novel protective role of BMAL1 in hepatocytes against ALD. The protective action of BMAL1 during alcohol consumption depends on its ability to couple ChREBP-induced de novo lipogenesis with PPARα-mediated fatty oxidation. (Hepatology 2018).

Purpose Chronic hepatitis B virus (HBV) infection is a key determinant of hepatocellular carcinoma (HCC). However, the mechanism by which HBV contributes to the development of HCC remains to be further explored. HBV-encoded miR-3 (HBV-miR-3) is a newly discovered microRNA that can affect the replication of HBV, but its influence on host genes is unclear. The tumor suppressor phosphatase and tensin homolog (PTEN) is expressed at low levels in most cancer cells. How HBV-miR-3 acts on PTEN to induce tumorigenesis has not been clarified. Materials and Methods PTEN protein expression was evaluated in HBV-miR-3-transfected cells and HBV-related liver cancer and paracancerous tissues. A luciferase reporter assay was employed to identify the HBV-miR-3 binding site on the 3ʹ-untranslated region (3ʹ-UTR) of PTEN. Cell apoptosis was assessed by flow cytometry. Cell proliferation was evaluated by colony formation assays. Transwell assays were used to detect cancer cell invasion. Results HBV-miR-3 was identified only in HBV-replicating HCC cells and HBV-infected patients. HBV-miR-3 expression in liver cancer tissues was higher than that in paracancerous tissues, and the corresponding PTEN expression was significantly decreased. Wild-type HBV-miR-3 bound to the 3ʹ-UTR of PTEN and downregulated its protein expression in a dose-dependent manner. Moreover, the inhibition of HBV-miR-3 rescued PTEN protein expression. Furthermore, HBV-miR-3 reduced liver cancer cell apoptosis, enhanced cell invasion, and promoted cell proliferation. Conclusion HBV-miR-3 binds to the 3ʹ-UTR of PTEN mRNA and downregulates PTEN protein expression, thereby reducing cell apoptosis and enhancing cell invasion and proliferation. These results indicate that HBV-miR-3 contributes to the development of HBV-related HCC and may be a therapeutic target for this cancer.

Prolonged ER stress has been known to be one of the major drivers of impaired lipid homeostasis during the pathogenesis of non‐alcoholic liver disease (NAFLD). However, the downstream mediators of ER stress pathway in promoting lipid accumulation remain poorly understood. Here, we present data showing the b‐ZIP transcription factor E4BP4 in both the hepatocytes and the mouse liver is potently induced by the chemical ER stress inducer tunicamycin or by high‐fat, low‐methionine, and choline‐deficient (HFLMCD) diet. We showed that such an induction is partially dependent on CHOP, a known mediator of ER stress and requires the E‐box element of the E4bp4 promoter. Tunicamycin promotes the lipid droplet formation and alters lipid metabolic gene expression in primary mouse hepatocytes from E4bp4flox/flox but not E4bp4 liver‐specific KO (E4bp4‐LKO) mice. Compared with E4bp4flox/flox mice, E4bp4‐LKO female mice exhibit reduced liver lipid accumulation and partially improved liver function after 10‐week HFLMCD diet feeding. Mechanistically, we observed elevated AMPK activity and the AMPKβ1 abundance in the liver of E4bp4‐LKO mice. We have evidence supporting that E4BP4 may suppress the AMPK activity via promoting the AMPKβ1 ubiquitination and degradation. Furthermore, acute depletion of the Ampkβ1 subunit restores lipid droplet formation in E4bp4‐LKO primary mouse hepatocytes. Our study highlighted hepatic E4BP4 as a key factor linking ER stress and lipid accumulation in the liver. Targeting E4BP4 in the liver may be a novel therapeutic avenue for treating NAFLD.