The acidic pathway of bile acid synthesis: Not just an alternative pathway(☆)

Over the last two decades, the prevalence of obesity, and metabolic syndromes (MS) such as non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM), have dramatically increased. Bile acids play a major role in the digestion, absorption of nutrients, and the body’s redistribution of absorbed lipids as a function of their chemistry and signaling properties. As a result, a renewed interest has developed in the bile acid metabolic pathways with the challenge of gaining insight into novel treatment approaches for this rapidly growing healthcare problem. Of the two major pathways of bile acid synthesis in the liver, the foremost role of the acidic (alternative) pathway is to generate and control the levels of regulatory oxysterols that help control cellular cholesterol and lipid homeostasis. Cholesterol transport to mitochondrial sterol 27-hydroxylase (CYP27A1) by steroidogenic acute regulatory protein (StarD1), and the subsequent 7α-hydroxylation of oxysterols by oxysterol 7α-hydroxylase (CYP7B1) are the key regulatory steps of the pathway. Recent observations suggest CYP7B1 to be the ultimate controller of cellular oxysterol levels. This review discusses the acidic pathway and its contribution to lipid, cholesterol, carbohydrate, and energy homeostasis. Additionally, discussed is how the acidic pathway’s dysregulation not only leads to a loss in its ability to control cellular cholesterol and lipid homeostasis, but leads to inflammatory conditions.