Study of alcoholic ketoacidosis in mice - Summary Alcoholic ketoacidosis is a metabolic complication caused by chronic/binge alcohol drinking in a state of poor nutrition. Chronic alcohol use depletes glycogen stores in the liver and impairs gluconeogenesis, causing decreased glucose availability and increased reliance on fatty acid breakdown. This also alters counterregulatory hormone balance that further increases free fatty acid breakdown and ketone production, resulting in metabolic acidosis. The main features of alcoholic ketoacidosis are low blood bicarbonate levels, high ketone bodies, and high anion gaps. Alcoholic ketoacidosis commonly causes tachycardia, agitation, abdominal pain, nausea and vomiting, and it can lead to death, if untreated. This metabolic disorder was first reported in 1940s and pathophysiological data were collected from patients taken several decades ago, which helped to lay the foundation for the current understanding of its pathophysiology, diagnosis, and management. Nonetheless, our understanding of alcoholic ketoacidosis is presently limited and has many challenges. No study has been conducted to test its cause and underlying mechanism. Understanding the mechanism is essential for developing a strategy to reduce the risk of alcoholic ketoacidosis. In preliminary studies, we successfully induced alcoholic ketoacidosis in mice by modifying the clinically relevant alcohol feeding protocol. Mice fed chronic/binge alcohol under a fasting condition develop low blood bicarbonate levels, high β- hydroxybutyrate, and a high anion gap, all of which are hallmarks for alcoholic ketoacidosis. These features do not occur by chronic-plus-binge alone or fasting alone. With the development of an animal model exhibiting alcoholic ketoacidosis, we are now in a great position to tackle this metabolic complication. The project has three specific aims. Aim 1 will examine additional parameters related to alcoholic ketoacidosis and then focus on testing whether the currently known causes (excessive alcohol use, poor nutrition, and dehydration) are valid. Aim 2 will examine the mechanism underlying the pathogenesis. Our hypothesis is that acidosis is induced not only by inadequate energy stores but also by downregulation of the pH-regulating protein NBCn1, and that this acidosis stimulates alcohol consumption in a feedback process and subsequently exacerbates the condition. The hypothesis will be tested by examining the effects of ketogenesis, decreased brain pH, and NBCn1 knockdown in the brain regions associated with alcohol reward, on alcoholic ketoacidosis. Aim 3 will test the NaHCO3-mediated intervention to reduce the risk of alcoholic ketoacidosis. The efficacy of sodium bicarbonate for reducing alcoholic ketoacidosis, its effect on alcohol reward, and the protective role in alcohol- induced liver injury will be investigated. The impact of the project is that the results will provide valuable information on alcoholic ketoacidosis that has been challenging. The results will also lead to a new research platform for the development of a non-prescription product that helps reduce excessive alcohol consumption for chronic/binge drinkers who could be metabolically complicated with alcoholic ketoacidosis.
