The Liver under the Spotlight: Bile Acids and Oxysterols as Pivotal Actors Controlling Metabolism

Abstract

Among the myriad of molecules produced by the liver, both bile acids and their precursors, the oxysterols are becoming pivotal bioactive lipids which have been underestimated for a long time. Their actions are ranging from regulation of energy homeostasis (i.e., glucose and lipid metabolism) to inflammation and immunity, thereby opening the avenue to new treatments to tackle metabolic disorders associated with obesity (e.g., type 2 diabetes and hepatic steatosis) and inflammatory diseases. Here, we review the biosynthesis of these endocrine factors including their interconnection with the gut microbiota and their impact on host homeostasis as well as their attractive potential for the development of therapeutic strategies for metabolic disorders.

Keywords: bile acids; cholesterol; glucose metabolism; gut microbiota; inflammation; lipid metabolism; liver; oxysterols; steatosis.

Figure 1

Overview of oxysterol and bile acid (BA) metabolism. (A) Structure of the main oxysterols and BAs involved in host homeostasis modulation. (B) Biosynthesis and circulation of oxysterols and BAs. (1) Primary BAs are generated from oxysterols through numerous enzymes (e.g., CYP7A1, CYP27A1, CYP7B1 and CYP8B1) in hepatocytes, are then conjugated with T or G by BAL and BAAT and finally stored in the gallbladder. (2) Upon meal ingestion, these are released into the duodenum. (3) BAs can facilitate lipid absorption. (4) Some primary BAs are deconjugated and then converted into secondary BAs by specific intestinal bacteria. (5) While approximately 5% are excreted, (6) about 95% are reabsorbed and travel back to the liver via the portal vein. (7) Finally, a small proportion of BAs reaches other organs (e.g., muscles and adipose tissue) through the systemic circulation. Abbreviations: BA, bile acid; BAAT, bile acid CoA:amino acid N-acyltransferase; Bai, bile acid-inducible; BAL, bile acid CoA ligase; BSH, bile salt hydrolase; CA, cholic acid; CDCA, chenodeoxycholic acid; CYP, cytochrome P450 enzyme; DCA, deoxycholic acid; G, glycine-conjugated species; HCA, hyocholic acid; HDCA, hyodeoxycholic acid; LCA, lithocholic acid; MCA, muricholic acid; MDCA, murideoxycholic acid; OHC, hydroxycholesterol; T, taurine-conjugated species; UDCA, ursodeoxycholic acid.

Figure 2

BAs and oxysterols at the nexus of host homeostasis. (A) BA profile in the intestine regulates lipid assimilation with 12-OH BAs promoting fat and cholesterol absorption. Conversely, the composition of the diet also influences BA profile since total BAs is increased upon high-fat diet (HFD) exposure. (B) A mutual relationship exists between the gut microbiota and BAs. BAs regulate the proliferation, maturation and the composition of the intestinal bacteria while the gut microbiota generates secondary BAs. Displaying a healthy equilibrium is essential since bacterial metabolites including secondary BAs are impacting host metabolism. (C) BAs and oxysterols are considered as signaling molecules since they can interact with a panel of receptors distributed in the whole body. The BA receptors FXR, TGR5 and VDR as well as the oxysterol receptor LXR are the most important ones regarding inflammatory and metabolic disorders. Abbreviations: BA, bile acid; CA, cholic acid; DCA, deoxycholic acid; FXR, farnesoid X receptor; GLP-1, glucagon-like peptide 1; LXR, liver X receptor; MCA, muricholic acid; OH, hydroxyl group; TGR5, Takeda G-protein coupled receptor 5; UDCA, ursodeoxycholic acid; VDR, vitamin D receptor.

Figure 3

Modulation of oxysterol and BA profiles by the hepatic endocannabinoid and immune system in male mice. BAs are cholesterol-derived bioactive lipids synthesized by two pathways in hepatocytes: the classic pathway (i.e., CYP7A1 and CYP8B1) and the alternative pathway (i.e., CYP27A1 and CYP7B1), this latter being the main route for oxysterol production. BA synthesis is under the regulation of a negative feedback loop. When FGF15, produced by enterocytes and secreted into the portal vein, binds to FGFR4/β-Klotho receptor, it induces the repression of BA production by activating ERK/JNK enzymes. Interestingly, this repression cascade seems also under the control of the immune system involving TLR/MyD88 complex. Finally, a reciprocal regulation might take place between BAs and NAPE-PLD, which is responsible for generating other crucial bioactive lipids named NAEs. Abbreviations: BA, bile acid; CYP27A1, sterol 27-hydroxylase; CYP7A1, cholesterol 7α-hydroxylase; CYP7B1, oxysterol 7α-hydroxylase; CYP8B1, sterol 12α-hydroxylase; ERK, extracellular signal-regulated kinase; FGF15, fibroblast growth factor 15; FGFR4, fibroblast growth factor receptor 4; JNK, c-Jun N-terminal kinase; MyD88, myeloid differentiation primary response gene 88; NAE, N-acylethanolamine; NAPE-PLD, N-acylphosphatidylethanolamine-selective phospholipase D; TLR, toll-like receptor.