Diabetes Metab J.  2019 Jun;43(3):257-272. 10.4093/dmj.2019.0043.

Understanding Bile Acid Signaling in Diabetes: From Pathophysiology to Therapeutic Targets

• Ferrell JM
• Chiang JY

• KMID: 2454055
• DOI: http://doi.org/10.4093/dmj.2019.0043

Abstract

Diabetes and obesity have reached an epidemic status worldwide. Diabetes increases the risk for cardiovascular disease and non-alcoholic fatty liver disease. Primary bile acids are synthesized in hepatocytes and are transformed to secondary bile acids in the intestine by gut bacteria. Bile acids are nutrient sensors and metabolic integrators that regulate lipid, glucose, and energy homeostasis by activating nuclear farnesoid X receptor and membrane Takeda G protein-coupled receptor 5. Bile acids control gut bacteria overgrowth, species population, and protect the integrity of the intestinal barrier. Gut bacteria, in turn, control circulating bile acid composition and pool size. Dysregulation of bile acid homeostasis and dysbiosis causes diabetes and obesity. Targeting bile acid signaling and the gut microbiome have therapeutic potential for treating diabetes, obesity, and non-alcoholic fatty liver disease.

Keyword

Bile acids and salts; Gastrointestinal microbiome; Non-alcoholic fatty liver disease; Receptors, cytoplasmic and nuclear; Receptors, G-protein-coupled

MeSH Terms

Bacteria
Bile Acids and Salts
Bile*
Cardiovascular Diseases
Dysbiosis
Gastrointestinal Microbiome
Glucose
Hepatocytes
Homeostasis
Intestines
Membranes
Non-alcoholic Fatty Liver Disease
Obesity
Receptors, Cytoplasmic and Nuclear
Receptors, G-Protein-Coupled
Bile Acids and Salts
Glucose
Receptors, Cytoplasmic and Nuclear
Receptors, G-Protein-Coupled

Figure

• 

  Fig. 1 Metabolic syndrome is a collection of five phenotypes: hypertension, hyperglycemia, hypertriglyceridemia, insulin resistance and obesity. Many of these metabolic phenotypes are associated with type 2 diabetes mellitus (T2DM). T2DM increases risk for cardiovascular disease (CVD) and non-alcoholic fatty liver disease (NAFLD). NAFLD is a spectrum of liver disease including simple steatosis, nonalcoholic steatohepatitis (NASH), liver fibrosis, cirrhosis, and hepatocellular carcinoma. Obesity, hepatic steatosis and insulin resistance all contribute to NAFLD.

• 

  Fig. 2 Bile acid synthesis, enterohepatic circulation of bile acids, and bile acid transport. In human hepatocytes, cholesterol 7α-hydroxylase (CYP7A1) catalyzes the first and rate-limiting step in the classic pathway of bile acid synthesis in which cholic acid (CA) and chenodeoxycholic acid (CDCA) are synthesized from cholesterol. Sterol 12α-hydroxylase (CYP8B1) is required for synthesis of CA, and without this enzyme CDCA is synthesized. The alternative pathway is initiated by sterol 27-hydroxylase (CYP27A1), which catalyzes steroid side-chain oxidation, followed by oxysterol 7α-hydroxylase (CYP7B1), which synthesizes the oxidized sterols that form CA and CDCA in hepatocytes. CYP7A1 is liver-specific, while CYP27A1 and CYP7B1 are expressed in extrahepatic tissues and macrophages. Bile acids are conjugated to the amino acids taurine (T) or glycine (G) for secretion into bile via bile salt export pump (BSEP). Bile acids are reabsorbed in the ileum via apical sodium-dependent bile acid transporter (ASBT) in enterocytes, where gut bacterial bile salt hydrolase (BSH) de-conjugates bile acids and 7α-dehydroxylase removes a hydroxyl group to form the secondary bile acids, deoxycholic acid (DCA) and lithocholic acid (LCA) from CA and CDCA, respectively. Bile acids are effluxed to portal blood via organic solute transporter α and β (OSTα/OSTβ) dimers and are transported to hepatocytes via Na2+-dependent taurocholate co-transporting peptide (NTCP) where they inhibit bile acid synthesis. Bile acids activate hepatic farnesoid X receptor (FXR) to induce small heterodimer partner (SHP), which inhibits CYP7A1 and CYP8B1 gene transcription. In enterocytes, bile acid activation of FXR induces fibroblast growth factor 19 (FGF19). FGF19 is transported to hepatocytes to activate FGF receptor 4 (FGFR4)/β-Klotho complex, which activates EKR1/2 signaling to inhibit CYP7A1 gene transcription. Bile acids activate Takeda G protein-coupled receptor 5 (TGR5) in intestinal L-cells, leading to secretion of glucagon-like peptide-1 (GLP-1), which stimulates insulin secretion from β-cells. In adipose tissue, activation of TGR5 stimulates cAMP/cAMP response element binding protein (CREBP) to induce thyroid hormone deiodinase type 2 (DIO2), which converts thyroxine (T4) to triiodothyronine (T3) and stimulates energy metabolism. ERK1/2, extracellular regulated kinase 1 and 2; PPARα, peroxisome proliferator-activated receptor α; GCA, glycocholic acid; GCDCA, glycochenodeoxycholic acid; TCA, taurocholic acid; TCDCA, taurochenodeoxycholic acid.

• 

  Fig. 3 Nutrient regulation of bile acid synthesis, insulin signaling, and mechanistic target of rapamycin complex 1 (mTORC1) signaling. Feeding induces cholesterol 7α-hydroxylase (CYP7A1) but inhibits sterol 12α-hydroxylase (CYP8B1), while fasting inhibits CYP7A1 but induces CYP8B1. Feeding and fasting cycles affect bile acid synthesis and composition, which in turn regulate hepatic lipid and glucose metabolism. After feeding and during the postprandial state, bile acids are released from the gallbladder to aid in nutrient absorption. In hepatocytes, CYP7A1 and bile acid synthesis are stimulated to activate farnesoid X receptor (FXR) signaling and insulin/insulin receptor substrate 1 (IRS1)-AKT-phosphoinositide 3-kinase (PI3K) signaling. Insulin signaling inhibits mTORC1/protein S6 kinase (S6K) signaling and steroid regulatory element binding protein 1c (SREBP1c)-mediated lipogenesis. During the late post-prandial state, FXR induces fibroblast growth factor 19 (FGF19) to inhibit CYP7A1 and bile acid synthesis via FGF receptor 4 (FGFR4)/β-Klotho/extracellular regulated kinase 1 and 2 (ERK1/2) signaling. During fasting and prolonged starvation, free fatty acids released from adipose triglycerides activate peroxisome proliferator-activated receptor γ (PPARγ) in adipose tissue and PPARα in hepatocytes, and induce FGF21. FGF21 induces peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) to stimulate mitochondrial oxidative phosphorylation and energy production. FGF21 also inhibits mTORC1 signaling to stimulate insulin signaling. In enterocytes, FXR induces ceramides, which activate mTORC1/S6K signaling and stimulate processing of full length SREBP1c to its nuclear form (nSREBP1), stimulating lipogenesis. During fasting, CYP8B1 is induced and increases synthesis of cholic acid (CA) and deoxycholic acid (DCA). DCA activates intestinal FXR and ceramide synthesis. CYP8B1 inhibits FGF21 and activates mTORC1 signaling via inhibition of PPARα. CDCA, chenodeoxycholic acid; TCA, taurocholic acid; TGR5, Takeda G protein-coupled receptor 5; CREBP, cAMP response element binding protein; DIO2, deiodinase type 2; T, taurine; TCDCA, taurochenodeoxycholic acid; LCA, lithocholic acid; DCA, deoxycholic acid.

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