Exploring Margaric Acid Role in Alcohol-Associated Liver Diseases

Alcohol-associated liver diseases (AALD) 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 AALD. 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 AALD. Therefore, the gut is a crucial target for developing therapeutics for AALD. A critical barrier in this field is that the mechanism underlying alcohol-induced TJ disruption is poorly defined. Our long-term goal is to describe the pathophysiology of AALD and develop novel therapeutic strategies by targeting gut barrier dysfunction. Our preliminary studies show that: 1) margaric acid levels in the plasma from patients with severe alcoholic hepatitis were significantly low compared to healthy subjects. 2) The plasma level of heptadecenoic acid (C17:1), the unsaturation metabolite of margaric acid, was increased in patients with severe alcoholic hepatitis. 3) Pretreatment of Caco-2 cell monolayers (an established model of the intestinal epithelium) with margaric acid-reduced ethanol (EtOH) and acetaldehyde (MeCHO)- induced TJ disruption and epithelial barrier dysfunction. 4) Margaric acid elevated Caco-2 cell rigidity (analyzed by atomic force microscopy) and attenuated EtOH and MeCHO-induced reduction of cell rigidity. These findings form the scientific premise and support the central hypothesis that margaric acid supplementation attenuates alcohol-induced gut and liver injury. We will test this hypothesis by determining that 1) Margaric acid dose- dependently attenuates alcohol-induced remodeling of the actin cytoskeleton in the intestinal epithelium, 2) Margaric acid prevents alcohol-induced disruption of TJ and AJ in the intestinal epithelium, 3) Margaric acid supplementation of the diet attenuates alcohol-induced gut and liver injury in a dose-dependent manner, and 4) Margaric acid (C17:0) to heptadecenoic acid (C17:1) ratio drives alcohol-induced gut and liver injury. The expected outcome of these studies will help establish the therapeutic potential of margaric acid in treating alcohol-associated diseases.