Effects of bile acids on neurological function and disease - PubMed (original) (raw)

Review

Effects of bile acids on neurological function and disease

Matthew McMillin et al. FASEB J. 2016 Nov.

Abstract

Bile acids are synthesized from cholesterol and are known to be involved with the emulsification and digestion of dietary lipids and fat-soluble vitamins. Outside of this role, bile acids can act as cell signaling effectors through binding and activating receptors on both the cell membrane and nucleus. Numerous reports have investigated these signaling pathways in conditions where the liver is damaged. More recently, effort has been made to investigate the role of bile acids in diseases outside of those associated with liver damage. This review summarizes recent findings on the influences that bile acids can exert in normal neurological function and their contribution to diseases of the nervous system, with the intent of highlighting the role of these metabolites as potential players in neurological disorders.-McMillin, M., DeMorrow, S. Effects of bile acids on neurological function and disease.

Keywords: FXR; TGR5; cholesterol; metabolism; neuroinflammation.

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Figures

Figure 1.

Figure 1.

Schematic representation of the classic, alternative, and neural cholesterol clearance pathways of bile acid synthesis. The classic pathway of bile acid synthesis is initiated from cholesterol by CYP7A1, which leads to the formation of 7α-hydroxycholesterol which, after some metabolic reactions, interacts with CYP8B1 or CYP27A1 to form cholic acid or chenodeoxycholic acid. The alternative pathway of bile acid synthesis begins with the metabolism of cholesterol to 27-hydroxycholesterol via CYP27A1. 27-Hydroxysterol is subsequently metabolized by CYP7B1 which, after a few metabolic steps leads to the synthesis of CDCA. The final pathway depicted is the neural cholesterol clearance pathway, which is initiated by the formation of 24(S)-hydroxycholesterol from cholesterol by CYP46A1. 24(S)-hydroxycholesterol subsequently exits the brain and enters the bloodstream where it is metabolized by CYP39A1 in the liver to continue bile acid synthesis.

Figure 2.

Figure 2.

Bile acid signaling through membrane-bound or nuclear receptors. Certain bile acids can bind the membrane receptors TGR5, S1PR2, and a5B1 integrin. Alternatively, bile acids may exert their effects through nuclear receptors. In order for bile acids to bind nuclear receptors, they need to passively diffuse across the cell membrane or are actively transported by ASBT, NTCP, or OATP. Once inside the cell, bile acids can bind FXR, VDR, PXR, GR, or CAR which facilitates DNA binding and subsequent regulation of transcription. Similar to the membrane bile acid receptors, these nuclear receptors have differential affinity for specific bile acids, which are indicated in this figure.

Figure 3.

Figure 3.

Summary of the effects of bile acid–mediated signaling on normal brain physiology and neurologic disorders.

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