UCLA researchers from the Department of Medicine and Division of Cardiology have identified target enzymes involved in bile acid synthesis and developed methods to improve disease outcomes in fatty liver and atherosclerosis.
BACKGROUND: Dietary fat is an essential, energy-dense nutrient necessary for survival. To support this, the intestinal system has evolved to absorb dietary fat with remarkable efficiency. Yet, with the increased production and consumption of processed, readily available, and high fat foods, this conserved efficiency has led to the development of obesity. Furthermore, the high percentage of saturated fatty acids in Western diets are implicated in associated metabolic disorders.
In the intestine, bile acids emulsify triglycerides into smaller lipid droplets and solubilize free fatty acids into micelles for absorption by enterocytes. Bile acids, initially synthesized from cholesterol in the liver, form a structurally diverse pool. The physicochemical properties of bile acids allow them actively regulate the fatty acid uptake process. Evolutionarily, bile acids appear to preferentially promote the uptake of polyunsaturated fatty acids over saturated fatty acids, given that the former are essential nutrients only obtained through the diet. Further, different diseases have distinct associated bile acid composition enabling lipid solubility and uptake. This makes exploring strategies to manipulate the bile acid pool a key therapeutic opportunity.
INNOVATION: UCLA researchers identified different enzymes in the bile acid synthesis pathway as effective targets to control dietary fat absorption. Modulation of bile acid levels by selectively targeting different enzymes facilitate the uptake of saturated fatty acids. By suppressing these enzymes via liver-directed gene editing, researchers were able to increase anorectic hormones and reduce food intake. Targeting the these bile acid synthetic enzymes helped protect against diet-induced obesity in ways solely targeting lipases cannot, and further impacted the uptake, distribution, and storage of lipids. Notably, reducing or altering bile acids also suppressed the secretion of incretin hormones, similar to the process induced by obesity management medications. Thus, this technology offers potential to improve patient outcomes in a variety of metabolic diseases.
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ADVANTAGES:
DEVELOPMENT-TO-DATE: Generated proof-of-concept data using genetic disruption of enzyme in mouse models, showing improved disease outcomes.
KEYWORDS: Bile acid, cardiometabolic disease, lipid absorption, fatty acid, fatty liver, obesity, atherosclerosis, enzymes