Role of Hepatitis B Virus Large Surface Protein in Promoting Activation of Nuclear SREBPs via ER Stress: Implications for Hepatocellular Carcinoma

One of the most common fatal malignancies in the world is Hepatocellular carcinoma (HCC) and hepatitis B virus (HBV) infection has been identified as a leading risk factor for HCC. Studies have suggested that during infection the large surface viral protein of HBV (LS protein) is targeted to the endoplasmic reticulum (ER) of the host liver cell, where its accumulation causes ER stress leading to HCC. The LS protein is also believed to stimulate the lipogenic activity of the ATP citrate lyase (ACL) enzyme, leading to excessive synthesis of lipids required for the rapidly dividing liver tumor cell. Here, I propose a hypothesis linking viral LS protein-induced ER stress to generation of the mature transcriptionally active nuclear form of sterol regulatory element-binding protein (nSREBP). nSREBP translocates to the nucleus and binds to sterol regulatory elements (SRE) present in the ATP citrate lyase (ACL) gene promoter, thereby elevating ACL transcription levels and overproduction of the ACL enzyme protein. Inhibition of LS protein activity in the ER may provide a therapeutic strategy in treating HBV induced HCC.