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Frontiers of Medicine

ISSN 2095-0217

ISSN 2095-0225(Online)

CN 11-5983/R

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2018 Impact Factor: 1.847

Front. Med.    2018, Vol. 12 Issue (6) : 608-623    https://doi.org/10.1007/s11684-018-0644-x
REVIEW |
Bile acids and their effects on diabetes
Cynthia Rajani1, Wei Jia1,2()
1. University of Hawaii Cancer Center, Honolulu, HI 96813, USA
2. Shanghai Key Laboratory of Diabetes Mellitus and Center for Translational Medicine, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai 200233, China
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Abstract

Diabetes is a widespread, rapidly increasing metabolic disease that is driven by hyperglycemia. Early glycemic control is of primary importance to avoid vascular complications including development of retinal disorders leading to blindness, end-stage renal disease, and accelerated atherosclerosis with a higher risk of myocardial infarction, stroke and limb amputations. Even after hyperglycemia has been brought under control, “metabolic memory,” a cluster of irreversible metabolic changes that allow diabetes to progress, may persist depending on the duration of hyperglycemia. Manipulation of bile acid (BA) receptors and the BA pool have been shown to be useful in establishing glycemic control in diabetes due to their ability to regulate energy metabolism by binding and activating nuclear transcription factors such as farnesoid X receptor (FXR) in liver and intestine as well as the G-protein coupled receptor, TGR5, in enteroendocrine cells and pancreatic β-cells. The downstream targets of BA activated FXR, FGF15/21, are also important for glucose/insulin homeostasis. In this review we will discuss the effect of BAs on glucose and lipid metabolism and explore recent research on establishing glycemic control in diabetes through the manipulation of BAs and their receptors in the liver, intestine and pancreas, alteration of the enterohepatic circulation, bariatric surgery and alignment of circadian rhythms.

Keywords bile acids      metabolic memory      diabetes      circadian rhythm      bariatric surgery     
Corresponding Authors: Wei Jia   
Just Accepted Date: 06 August 2018   Online First Date: 16 October 2018    Issue Date: 03 December 2018
 Cite this article:   
Cynthia Rajani,Wei Jia. Bile acids and their effects on diabetes[J]. Front. Med., 2018, 12(6): 608-623.
 URL:  
http://academic.hep.com.cn/fmd/EN/10.1007/s11684-018-0644-x
http://academic.hep.com.cn/fmd/EN/Y2018/V12/I6/608
Fig.1  The Effects of hyperglycemia on the development of metabolic memory. Excess glucose can exceed glycogen storage capacity and use for energy. When this happens, several alternative glucose utilizing pathways become active. The polyol or aldose reductase pathway converts glucose to sorbitol with concurrent production of additional NADH which when reacted with NADH oxidase leads to the production of excess ROS ultimately causing mitochondrial dysfunction. Sorbitol can also be converted to fructose in the polyol pathway and enter the glycolytic pathway to become F-6-P and then onto F-1,6-bis-P which in turn can become converted to GA3P and then methylglyoxal, a precursor for AGEs. Alternatively, F-1,6-bis-P can be biotransformed into DHAP which then enters 2 cycles, one which leads back to F-1,6-bis-P and more AGEs and another which leads to synthesis of G-3-P which can go on to be converted to DAG. DAG blocks AKT→ IRS1/2 leading to decreased insulin sensitivity. In the glycolytic pathway, G-6-P can be diverted to the hexosamine pathway which leads to an increase in O-GlcNAc proteins that in turn can cause increased insulin resistance, gluconeogenesis and lipogenesis [2,6,810]. Abbreviations: hexokinase (HK), glucose-6-phosphate (G-6-P), fructose-6-phosphate (F-6-P), fructose-1,6-bis-phosphate (F-1,6-bis-P), glyceraldehydes-3-phosphate (GA3P), advanced glycosylation end products (AGEs), reactive oxygen species (ROS), dihydroxyacetone phosphate (DHAP), O-linked-N-acetylglucosamine (O-GlcNAc), glucosamine-fructose-6-phosphate aminotransferase (GFAT), glucose-3-phosphate (G3P), glucose-3-phosphate dehydrogenase (G-3-P DH), diacylglycerol (DAG), protein kinase C (PKC), protein kinase B (AKT), insulin receptor substrate 1/2 (IRS1/2), insulin receptor (IR), forkhead box protein O1 (FoxO1), carbohydrate response element binding protein (ChREBP), phosphoenolate pyruvate carboxylase (PEPCK).
Fig.2  The effects of BAs on glucose and lipid metabolism in the normal liver. BAs are considered positive regulators of metabolism in the liver. BA activation of FXR causes its translocation to the nucleus where it forms a heterodimer with RXR. Several signaling pathways are initiated as a result. The co-factor, SHP becomes active in binding the transcription factor, HNF4 which in turn, releases its co-factor CBP. This results in inhibition of the transcription of two important enzymes in gluconeogenesis, PEPCK and FBP1. SHP also can bind to the transcription factor FoxO1 which in turn releases its co-factor, CBP with the result that the enzyme G6Pase does not get expressed. In this way BA activated FXR inhibits gluconeogenesis and prevents release of more glucose into the circulation. BA activated FXR also modulates the transcription factor LXR. LXR is a positive regulator of the transcription factors, ChREBP and SREBP1c which act synergistically to control DNL and glycolysis. Both insulin and glucose can also activate LXR directly. FXR is a negative regulator of LXR and thus BAs via FXR have the effect of decreasing TG formation and accumulation in the liver. Decreased glycolysis leading to pyruvate may also lead to increased shunting into the glycogenesis pathway. BA activated FXR also increases expression of the transcription factor PPARα which leads to increased transcription of genes important for β-oxidation of FAs, therefore increasing the use of FAs for energy rather for storage. PPARα activation also has the effect of stimulating the expression of FGF21 which has important ant-diabetic effects in adipose (Fig. 3) tissue. Lastly, FXR controls the transcription of genes important in lipid handling and transport such as increased expression of ApoCII which increases the activity of LPL and therefore more FAs are taken up by adipose, thus lowering plasma TGs. FXR also causes increased production of ApoA5 which acts to reduce hepatic uptake of TGs. FXR last of all, causes decreased expression of ApoCIII which has the effect of increasing FA uptake by the liver and thus lowers serum FA levels [11,2427]. Abbreviations: bile acid (BA), farnesoid X receptor (FXR), glucose receptor 2 (GLUT2), glucokinase (GK), glucose-6-phosphate (G6P), phosphoenolpyruvate (PEP), pyruvate kinase (PK), acetyl-CoA carboxylase (ACC), fatty acid synthase (FAS), steroyl-CoA-desaturase-1 (SCD1), liver X receptor (LXR), sterol response element binding protein-1c (SREBP1c), carbohydrate response element binding protein (ChREBP), retinoic acid receptor (RXR), fibroblast growth factor (FGF21), small heterodimer partner (SHP), hepatic nuclear factor-4 (HNF4), cAMP response element binding protein (CBP), forkhead transcription factor FoxO1 (FoxO1), glucose-6-phosphatase (G6Pase), phosphoenolatepyruvate carboxylase (PEPCK), fructose-1,6-bis-phosphatase (FBP1).
Fig.3  The effect of BAs on FGF19/21 and ceramide signaling relative to lipid and glucose metabolism. BA activated FXR has tissue specific effects with respect to hormone production. In the intestine, BAs activate FXR to cause production of FGF21 which is then secreted from the liver and binds to its receptor, FGFR4/β-Klotho on WAT causing activation of the ERK1/2→ RSK →Elk1/SRF pathway which in turn, causes increased expression of GLUT1 receptors on the adipocyte surface thus reducing hyperglycemia by increasing glucose uptake into the cell. FGF21 in WAT also causes increased secretion of adiponectin which has the effect of decreasing serum ceramide levels and increasing the number of beige of adipocytes thereby, increasing the energy utilization capabilities of the adipose tissue to help fight obesity. In the liver, FGF21 stimulates β-oxidation of FAs, as well as, increased ketogenesis. BA activation of FXR in the intestine targets two genes for enzymes important for the synthesis of ceramide, Smpd3 and Sptlc2, leading to increased serum levels of ceramide. In addition to the previously discussed effect on WAT, ceramide, when it is taken up by the liver becomes an activator of several signaling pathways which together act to block insulin signaling, hence, insulin resistance results. Ceramide also directly acts on the transcription factor, SREBP-1c, to increase DNL and lipid synthesis. The other consequence of intestinal FXR activation is the production on FGF19 which is secreted and then binds to its receptor, FGFR4/β-Klotho, in the liver where it acts to decrease BA synthesis and activates a hepatic ERK1/2 signaling pathway which results in increased protein synthesis, including GLUT1 receptors to increase glucose uptake and also increased glycogen synthesis to increase storage of glucose as glycogen. Both effects act to decrease hyperglycemia [28,32,3638]. Abbreviations: bile acid (BA), cholic acid (CA), chenodeoxycholic acid (CDCA), farnesoid X receptor (FXR), retinoid X receptor (RXR), fibroblast growth factor 19/21 (FGF19/21), insulin receptor (IR), insulin receptor substrate 1/2 (IRS1/2), inhibitor of nuclear factor kB kinase subunit β (IKK2), c-Jun N-terminal kinase (JNK), protein kinase C ζ (PKCζ), fatty acid (FA), protein kinase B (AKT), sterol response element binding protein-1c (SREBP1c), carbohydrate response element binding protein (ChREBP), S6 ribosomal protein (S6), eukaryotic translation initiator factor-4B (elF-4B), glycogen synthase kinase 3 (GSK3), glycogen synthase (GS), ribosomal S6 kinase (RSK), extracellular signal-related kinase 1/2 (ERK1/2), fibroblast growth factor receptor-4 (FGFR4), ETS domain containing protein-1 (Elk1), serum response factor (SRF), bile salt hydrolase (BSH), white adipose tissue (WAT), GLUT1 glucose transporter (GLUT1).
FGF-19 1° Targets 2° Targets Cellular effects Metabolic effects
Originates from BA activation of intestinal FXR Hepatic FGFR4/β-Klotho receptor complex ERK1/2 ↓Hepatic BA synthesis ↓BA concentrations in liver and gut
RSK ↑Hepatic GLUT1 receptors ↑Hepatic glucose uptake
↓Blood sugar
GSK3 ↑Glycogen synthase ↑Glycogen synthesis/storage from glucose
↓Blood sugar
FGF-21 1° Targets 2° Targets Cellular effects Metabolic effects
Originates from BA activation of hepatic FXR Adipose FGFR4/β-Klotho receptor complex ERK1/2+ RSK ↑Adipose GLUT1
receptors
↑Adipose glucose uptake
↓Blood sugar
↑Adiponectin secretion ↓Serum ceramide concentration
↑Number of beige adipocytes ↑Energy utilization by adipocytes
↓Lipid storage/obesity
PPARa/FGF21 synergism with PPARα agonists in WAT Upregulation of Ucp1 and Pgc1α in WAT but not BAT ↑Production of beige adipocytes in WAT ↑β-oxidation of FAs
↑Ketogenesis
↓Lipid storage/obesity
↓Blood sugar
↓Blood insulin
Tab.1  Effects of FGF-19/21 on metabolism [32, 36, 37, 42]
Tissue FGF15 Conclusion for FGF15 FGF21 Conclusion for FGF21
Liver KO (KlbAlb mice)/ treatments ↓CYP7A1
↓FGF15/βKlotho-FGFR4 signaling
FGF15/FGFR4 essential for BA homeostasis No acute effect on CYP7A1, ERK1/2 No acute, direct effect on hepatocytes
HFD (7 days) DIO both for KO and control with no changes in glucose production, uptake despite elevated FGF15 Hepatic FGF15 not essential for systemic glucose metabolism
2-week administration of FGF15/21 ↓Body weight, serum glucose, hepatic TG Improved metabolic parameters do not require FGF15/21 in liver ↓Body weight, serum glucose, hepatic TG Improved metabolic parameters do not require FGF15/21 in liver
Adipose KO (BAT,WAT)
Klbadipo mice/ longterm treatment FGF15/21
↑Whole body insulin sensitivity
↓Body weight, plasma insulin/glucose, hepatic TGs
↓Hepatic DAG for both control and model mice
↑Expression of Dusp4 in control mice only
The effects of these hormones do not require direct action on the adipocytes in Klbadipo mice but do directly affect ERK1/2 signaling in control mice ↑Whole body insulin sensitivity
↓Body weight, plasma insulin/glucose, hepatic TGs
↓Hepatic DAG for both control and model mice
↑Expression of Dusp4 in control mice only
The effects of these hormones do not require direct action on the adipocytes in Klbadipo mice but do directly affect ERK1/2 signaling in control mice
NS KO (KlbCamk2a mice)
Longterm treatment FGF15
Only control mice showed weight loss and improved glycemic control
Sympathetic nerve activity in BAT was ↑ in a dose dependent way with FGF15 treatment
FGF15 acts on the NS in a way similar to FGF21 (previous study)[45]
Administration of bFKB1 Ab to the FGFR1 receptor KlbCamk2a mice were resistant to weight loss and improved gylycemic control This confirmed the result in the FGF15/21 model βKlotho/FGFR1 complexes are essential in the NS
Tab.2  Effects of tissue-specific β-Klotho loss of function in mouse liver, adipose and nervous system on the nervous system relative to a floxed control [19]
Fig.4  The effects of BA activated TGR5 signaling in enteroendocrine cells (EECs) and in pancreatic β-cells. (A) EECc produce and secrete important hormones that affect energy metabolism and preserve pancreatic β-cell function. In EECs, TGR5 and GPR119 are coupled to Gαs G-proteins while GPR40 is coupled to a Gαq G-protein. Secondary BAs are agonists for TGR5 while 2-MAG and LCFAs are agonists for GPR119 and GPR40, respectively. All three GPCRs promote secretion of GLP-1, GIP and PYY, incretins that have important effects on glucose homeostasis. Gαs protein coupling to TGR5 and GPR119 results in the recruitment of adenyl cyclase which subsequently activates cAMP to increase intracellular Ca2+ via PKA or Epac pathways and ultimately increase secretion of GLP-1 and other incretins. Gαq protein coupling to GPR40 activates an alternate pathway to increase intracellular Ca2+ , PLC → IP3. Furthermore, Gαq signaling via PLC can activate DAG →PKC to cause increased incretin secretion via a Ca2+ independent pathway. It was determined that both Gαs and Gαq coupling to GPCRS worked in a synergistic way to increase intracellular Ca2+ levels which in turn stimulated vesicle fusion and increased secretion of incretins. (B) In the pancreatic β-cell, the BA TUDCA was used to activate TGR5 and this was found not only to increase the secretion of insulin via Ca2+ stimulated exocytosis using the same mechanism as seen in EECs for increased incretin secretion but TGR5 activation also led to activation of the CREB→ Bcl2/BclXL pathway to decrease apoptosis and additionally, activation of the CREB → IRS-2 → PDX pathway which leads to increased maturation of β-cells. The net result of these pathway activations is increased β-cell mass. TUDCA activation of TGR5 also activates ATF-4 → Gadd34 →elF2α signaling to cause increased protein translation which acts to decrease ER stress [46−52]. Abbreviations: lithocholic acid (LCA), deoxycholic acid (DCA), adenosine triphosphate (ATP), cyclic adenosine monophosphate (cAMP), protein kinase A (PKA), guanine nucleotide exchange factor (Epac), ryanodine receptor (RYR), long chain fatty acid (LCFA), inositol triphosphate (IP3), inositol triphosphate receptor (IP3R), endoplasmic reticulum (ER), diacylglycerol (DAG), phospholipase C (PLC), protein kinase C (PKC), peptide YY (PYY), glucose dependent insulintropic polypeptide protein (GIP), glucagon-like peptide-1 (GLP-1), hydroxysterol dehydrogenase (HSDH), chenodeoxycholic acid (CDCA), tauroursodeoxycholic acid (TUDCA), cAMP response element binding protein (CREB), activating transcription factor-4 (ATF-4), B cell lymphoma-2 (Bcl-2), B cell lymphoma extra large (BclXL), pancreatic and duodenal homeobox-1 (PDX1), insulin receptor substrate-2 (IRS2), growth arrest and DNA damage induced protein-34 (Gadd34), eukaryotic initiation factor 2α (elF2α).
Fig.5  The circadian control of BA synthesis, lipogenesis and the Octn1 transporter. In hepatocytes, there exists a circadian core clock that consists of an autoregulated feedback loop of rhythmically expressed genes that oscillate within a 24 h period. Two important genes, Clock and Bmal1 comprise the forward segment of the clock loop. CLOCK and BMAL1 proteins form a heterodimer which then bind to the DNA response element, E-box, to cause the transcription of Per and Cry genes. PER and CRY proteins then re-enter the nucleus and inhibit CLOCK:BMAL1 protein activity to reduce their own transcription. There is further regulation of the feedback loop by the nuclear hormone receptors, Rev-erbα which negatively regulates and RORα that positively regulates Bmal1 transcription [70]. REV-ERBα effects on BA metabolism include feeding independent circadian control of SREBP2, SREBP1c, the transcription factors for enzymes involved in lipogenesis and cholesterol-7α-hydroxylase (CYP7A1), the rate-limiting enzyme for BA synthesis in the liver. Transcription of a key protein, Insig2 is blocked by REV-ERBα and this causes increased release of SREBP from the ER and allows it to translocate into the nucleus. The circadian rhythm of SREBP2 causes corresponding changes in oxysterol production which are known to regulate LXR and increase transcription of Cyp7a1 [68]. Both PPARα and the co-activator, peroxisome proliferator-activated receptor gamma co-activator 1-α (PGC1α) modulate Bmal1 transcription [64,70]. PPARα is a positive regulator of the Octn1 transporter via control of transcription of the Slc22a4 gene [71]. In addition, certain nutrient-sensitive signaling pathways such as SIRT1 and AMPK couple metabolic flux to the circadian cycle [70]. Abbreviations: circadian locomotor output cycles kaput (Clock), brain and muscle Arnt-like 1 (Bmal1), period (Per), cryptochrome (Cry), reverse-erythroblastosis α (Rev-erbα), retinoic acid-related orphan receptor α (RORα), cholesterol-7α-hydroxylase (CYP7A1), sterol response element binding protein (SREBP). liver X receptor (LXR, peroxisome proliferator-activated receptor α(PPARα), peroxisome proliferator-activated receptor gamma co-activator 1-α (PGC1α), insulin-induced gene-2 (Insig2), SREBP-cleavage activating protein (SCAP), adenosine monophosphate-activated protein kinase (AMPK), nicotinamide adenine dinucleotide (NAD), sirtuin 1 (SIRT1), casein kinase 1(CK1), F-box/LRR repeat protein 3 (FBLX3), organic cation transporter novel type-1 (Octn1).
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