Defining the Role of Intestinal Calcium Channels in Alcoholic Liver Damage

Overview

Alcohol-related diseases and disorders (ADD) account for over 5% of global health problems, and alcohol abuse is a causal factor in more than 200 diseases. Endotoxemia and systemic inflammation are common conditions associated with morbidity and mortality in various ADD. Extensive clinical and experimental evidence indicates that disruption of intestinal epithelial tight junction and mucosal barrier dysfunction are prerequisite steps in alcoholic endotoxemia, systemic inflammation, and ADD. A critical barrier in the field is that the mechanisms of alcohol-induced tight junction disruption are poorly defined. Hence, the current treatment for ADD remains empiric (e.g., corticosteroids). Our long-term goal is to describe the pathophysiology of ADD and develop novel therapeutic strategies by targeting gut barrier dysfunction. TRPV6 and CaV1.3 are Ca2+ permeable ion channels on the apical membrane of the intestinal epithelium. Our preliminary studies have identified that: 1) Calcium influx from the apical membrane is required for the synergistic disruption of intestinal epithelial tight junction and barrier dysfunction by alcohol. 2) TRPV6 or CaV1.3 deficiency attenuates alcohol-induced epithelial permeability. 3) TRPV6 is required for alcohol-induced elevation of intracellular calcium, 4) alcohol evokes ionic currents in Caco-2 cells sensitive to SOR-C13, a TRPV6 inhibitor. 5) TRPV6 or CaV1.3 deficient mice are resistant to alcohol-induced gut permeability. 6) SORC13 prevents the alcohol-mediated epithelial permeability. These findings form the scientific premise and support the central hypothesis that TRPV6 and CaV1.3 channels drive alcohol-induced endotoxemia and systemic inflammation by enforcing intestinal epithelial TJ disruption and mucosal barrier dysfunction. We will test this hypothesis by determining that 1) the coordinated activities of TRPV6 and CaV1.3 channels mediate alcohol-induced rise in cellular calcium in the intestine, 2) TRPV6 and CaV1.3 channels mediate alcohol induced gut permeability, endotoxemia, and systemic inflammation, and 3) evaluate the preventive and mitigating potential of SOR-C13 and diltiazem, the calcium channel blockers, in alcohol-induced endotoxemia and systemic response. The expected outcome of these studies will be a deeper understanding of the intestine’s role in the pathophysiology of ADD and the identification of rationally designed novel therapeutic targets for the prevention and treatment of ADD.