Bile acids and sphingosine-1-phosphate receptor 2 in hepatic lipid metabolism

Abstract

The liver is the central organ involved in lipid metabolism. Dyslipidemia and its related disorders, including non-alcoholic fatty liver disease (NAFLD), obesity and other metabolic diseases, are of increasing public health concern due to their increasing prevalence in the population. Besides their well-characterized functions in cholesterol homoeostasis and nutrient absorption, bile acids are also important metabolic regulators and function as signaling hormones by activating specific nuclear receptors, G-protein coupled receptors, and multiple signaling pathways. Recent studies identified a new signaling pathway by which conjugated bile acids (CBA) activate the extracellular regulated protein kinases (ERK1/2) and protein kinase B (AKT) signaling pathway via sphingosine-1-phosphate receptor 2 (S1PR2). CBA-induced activation of S1PR2 is a key regulator of sphingosine kinase 2 (SphK2) and hepatic gene expression. This review focuses on recent findings related to the role of bile acids/S1PR2-mediated signaling pathways in regulating hepatic lipid metabolism.

Keywords: ABC, ATP-binding cassette; AKT/PKB, protein kinase B; BSEP/ABCB11, bile salt export protein; Bile acid; CA, cholic acid; CBA, conjugated bile acids; CDCA, chenodeoxycholic acid; CYP27A1, sterol 27-hydroxylase; CYP7A1, cholesterol 7α-hydroxylase; CYP7B1, oxysterol 7α-hydroxylase; CYP8B1, 12α-hydroxylase; DCA, deoxycholic acid; EGFR, epidermal growth factor receptor; ERK, extracellular regulated protein kinases; FGF15/19, fibroblast growth factor 15/19; FGFR, fibroblast growth factor receptor; FXR, farnesoid X receptor; G-6-Pase, glucose-6-phophatase; GPCR, G-protein coupled receptor; HDL, high density lipoprotein; HNF4α, hepatocyte nuclear factor-4α; Heptic lipid metabolism; IBAT, ileal sodium-dependent bile acid transporter; JNK1/2, c-Jun N-terminal kinase; LCA, lithocholic acid; LDL, low-density lipoprotein; LRH-1, liver-related homolog-1; M1–5, muscarinic receptor 1–5; MMP, matrix metalloproteinase; NAFLD, non-alcoholic fatty liver disease; NK, natural killer cells; NTCP, sodium taurocholate cotransporting polypeptide; PEPCK, PEP carboxykinse; PTX, pertussis toxin; S1P, sphingosine-1-phosphate; S1PR2, sphingosine-1-phosphate receptor 2; SHP, small heterodimer partner; SPL, S1P lyase; SPPs, S1P phosphatases; SRC, proto-oncogene tyrosine-protein kinase; SphK, sphingosine kinase; Sphingosine-1 phosphate receptor; Spns2, spinster homologue 2; TCA, taurocholate; TGR5, G-protein-coupled bile acid receptor; TNFα, tumor necrosis factor α; VLDL, very-low-density lipoprotein.

Graphical abstract

Figure 1

Bile acid synthesis and metabolism. Two major pathways are involved in bile acid synthesis. The neutral (or classic) pathway is controlled by CYP7A1 in the endoplasmic reticulum. The acidic (or alternative) pathway is initiated by sterol CYP27A1 in mitochondria. CYP8B1 is required to synthesize CA. Oxysterol 7α-hydroxylase (CYP7B1) is involved in the formation of CDCA in the acidic pathway. The neutral pathway is also able to form CDCA by CYP27A1. Primary bile acids are metabolized by gut bacteria to form the secondary bile acids, DCA and LCA.

Figure 2

Sphingosine-1-phosphate-mediated signaling pathways. Intracellular S1P is synthesized from sphingosine by SphK1. S1P can be converted back to sphingosine by S1P phosphatases (SPPs) or degraded to ethanolamine-1-phosphate and hexadecenal by SPL. Intracellular S1P can directly activate various cellular signaling pathways or be exported out of cells by specific transporters in the cell membrane. Extracellular S1P exerts its biological functions through activation of five G-protein coupled receptors, which are coupled to different G proteins and activate different cellular responses.

Figure 3

Conjugated bile acids regulate sterol and lipid metabolism via activating S1PR2. In hepatocytes, CBA activates the S1PR2 on the cell membrane, which induces the activation of ERK1/2 through activation of Gi protein. Activation of Gi will further induce activation of SRC, which can activate the matrix metalloproteinase (MMP) and EGFR. EGFR-induced ERK1/2 activation can directly activate gene transcription in the nucleus or further induce the activation of nuclear SPHK2 and the increase of nuclear S1P levels. Nuclear S1P is a strong inhibitor of nuclear HDAC1/2. Inhibition of HDAC will increase the acetylation and transcription of a lot of genes involved in nutrient and lipid metabolism such as CYP7A1, SREBP1c and ApoB-100.