Page 155 - Human Bile Acid Metabolism: a Postprandial Perspective

Figure 3: Effects of TGR5 activation in various tissues
Review: clinical relevance of TGR5
GLP-1 secretion
Preclinical
TGR5 is expressed on L cells and intestinal epithelium. L cells secrete GLP-1 in response to bile acids or selective agonists, leading to improved glucose tolerance and increased satiety.
Clinical
Rectal infusion studies confirm glucose-dependent secretion of GLP-1 in human beings. Selective agonism with SB-756050 did not give a conclusive outcome.
Insulin secretion
Preclinical
LCA stimulation of human and mouse β cells in vitro leads to increased glucose-dependent and glucose-independent insulin release. Both TGR5 and FXR are expressed on β cells.
Clinical
No evidence in human beings.
TGR5 is expressed on astrocytes and neurons, and its function is currently unknown. TGR5 on peptidergic neurons of dorsal root ganglia in the spinal cord transmits itching signals
TGR5
Thermogenesis
Preclinical
TGR5 is expressed in adipocytes and myocytes. Expression of UCP1 is increased. Thyroid hormone conversion in brown adipose tissue and muscle
is increased. Resistance to high-fat feeding-induced weight gain.
Clinical
Bile acids are associated with weight loss in patients that have undergone RYGB. Coexpression of TGR5/DIO2 occurs on myocytes but not on adipocytes. Fasting bile acid levels are not correlated with energy expenditure. Brown adipose tissue is probably not the primary physiological site of thermoregulation.
Inflammation
Preclinical
TGR5 is expressed on Kupffer and B cells, monocytes, macrophages, sinusoidal and vascular endothelium. Stimulation with
bile acids or specific antagonists decreases cytokine release and inflammation through the NFκB pathway. Inflammation in colitis, atherosclerosis, and liver inflammation models are decreased.
Clinical
Inflamed colon tissue from patients with Crohn’s disease is infiltrated with TGR5-expressing monocytes. TGR5 expression is not affected
by obesity or a high-fat diet
LCA=lithocholic acid. RYGB=Roux-en-Y gastric bypass.
Clinical data
Tgr5 is expressed in human BAT, and coexpression of Tgr5 and Dio2 has been
shown, suggesting that the bile acid–TGR5–DIO2 pathway is present in human
BAT.68 However, rodents and human beings are fundamentally different when it
comes to thermoregulation (figure 3). Rodents depend on thermogenesis in BAT to 8 maintain core body temperature, whereas the physiological role of BAT in human
beings is only partially understood. In rodents, BAT is mostly located in a few well-circumscribed compartments, and is reliably activated upon cold exposure. In human beings, these compartments are quite small and scarce; additionally not all human beings show the same thermogenic response to cold.69
Human skeletal muscle cells also coexpress Tgr5 and Dio2, and can be activated in vitro by stimulation with bile acids or a specific TGR5 agonist.1 In vivo, resting energy expenditure has been positively correlated with fasting concentrations of bile acids in lean healthy men; particularly with deoxycholic acid, which is a potent TGR5 stimulator.8,70 However, Brufau and colleagues71 found no correlation between fasting bile acid concentrations and resting energy expenditure in patients with cirrhosis, patients with type 2 diabetes, or matched controls. Orally delivered
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