Alcohol and Viral Hepatitis: Role of Lipid Rafts

Abstract

Both alcohol abuse and infection with hepatitis viruses can lead to liver disease, including chronic hepatitis. Alcohol and hepatitis viruses have synergistic effects in the development of liver disease. Some of these involve the cellular membranes and particularly their functionally active domains, termed lipid rafts, which contain many proteins with essential roles in signaling and other processes. These lipid rafts play a central role in the lifecycles of hepatitis viruses. Alcohol's actions at the lipid rafts may contribute to the synergistic harmful effects of alcohol and hepatitis viruses on the liver and the pathogenesis of liver disease.

Figure 1

The life cycle of hepatitis B virus (HBV) and the role of lipid rafts. The HBV particles consist of an inner core particle (i.e., the nucleocapsid) that is made up of several envelope proteins, core proteins, and viral DNA. It is surrounded by a membrane derived from the previous host cell. (1) The virus particle attaches, presumably via the Pre-S1 protein, to unknown HBV receptors in the membrane of the cell. These receptors are located in membrane regions with characteristic lipid composition (i.e., lipid rafts). (2) The virus particle is taken up into the cell via a process called endocytosis and the nucleocapsid is released. (3) The nucleocapsid is transported into the nucleus, where (4) the DNA is released and (5) transcribed into mRNAs. (6) Some of the mRNAs are translated into the envelope proteins in the endoplasmic reticulum (ER). (7) Other mRNAs are translated into core proteins in the host cell’s cytosol. (8) Envelope proteins, core proteins, and mRNA move to the Golgi apparatus and assemble into immature core particles. (9) The immature particles mature in the Golgi apparatus, including reverse transcription of viral mRNA into DNA. (10) The mature particles become surrounded by the Golgi apparatus membrane. (11) The mature particles are released from the host cell, taking a piece of cellular membrane with them as an envelope, including lipid raft pieces.

Figure 2

The life cycle of hepatitis C virus (HCV) and the role of lipid rafts. HCV particles attach to receptors in lipid-raft regions of the hepatocyte membrane, and the virus particles are taken up into the cell via endocytosis. The viral RNA is released and serves as template for the production of viral proteins at a structure called the membranous web, which also includes the membranes surrounding the endoplasmic reticulum (ER) and Golgi apparatus. The membranous web also is the site of assembly of new virus particles. During assembly and subsequent release of the viral particles, the particles obtain pieces of the cellular membrane as an outer envelope that shares the lipid composition of the membrane, particularly of the lipid rafts.

Figure 3

Alcohol’s effects on virus-infected hepatocytes. Alcohol may exert its effects both directly and indirectly. Indirect effects are, for example, related to the actions of the alcohol metabolite, acetaldehyde. Alcohol can directly affect both lipids and proteins in the cell. Through a variety of mechanisms, these effects may alter the infectivity of and the cell’s response to HBV and HCV, affecting both viral entry into the cells and release of viral particles from the cells.