Ursodeoxycholic Acid but Not Tauroursodeoxycholic Acid Inhibits Proliferation and Differentiation of Human Subcutaneous Adipocytes

Abstract

Stress of endoplasmic reticulum (ERS) is one of the molecular triggers of adipocyte dysfunction and chronic low inflammation accompanying obesity. ERS can be alleviated by chemical chaperones from the family of bile acids (BAs). Thus, two BAs currently used to treat cholestasis, ursodeoxycholic and tauroursodeoxycholic acid (UDCA and TUDCA), could potentially lessen adverse metabolic effects of obesity. Nevertheless, BAs effects on human adipose cells are mostly unknown. They could regulate gene expression through pathways different from their chaperone function, namely through activation of farnesoid X receptor (FXR) and TGR5, G-coupled receptor. Therefore, this study aimed to analyze effects of UDCA and TUDCA on human preadipocytes and differentiated adipocytes derived from paired samples of two distinct subcutaneous adipose tissue depots, abdominal and gluteal. While TUDCA did not alter proliferation of cells from either depot, UDCA exerted strong anti-proliferative effect. In differentiated adipocytes, acute exposition to neither TUDCA nor UDCA was able to reduce effect of ERS stressor tunicamycin. However, exposure of cells to UDCA during whole differentiation process decreased expression of ERS markers. At the same time however, UDCA profoundly inhibited adipogenic conversion of cells. UDCA abolished expression of PPARγ and lipogenic enzymes already in the early phases of adipogenesis. This anti-adipogenic effect of UDCA was not dependent on FXR or TGR5 activation, but could be related to ability of UDCA to sustain the activation of ERK1/2 previously linked with PPARγ inactivation. Finally, neither BAs did lower expression of chemokines inducible by TLR4 pathway, when UDCA enhanced their expression in gluteal adipocytes. Therefore while TUDCA has neutral effect on human preadipocytes and adipocytes, the therapeutic use of UDCA different from treating cholestatic diseases should be considered with caution because UDCA alters functions of human adipose cells.

Characterization of a novel bile acid-based delivery platform for microencapsulated pancreatic β-cells

“…Such eff ects may support our fi ndings ( Figure 2). However, other published work showed an inhibitory eff ect of UDCA on proliferation and diff erentiation of human subcutaneous adipocytes (Malisova et al 2013). Th e in vivo impact of UDCA on β -cell biochemical and bioinfl ammatory reactions is outside the scope of this study, but transplantation of our microencapsulated LVSA-PLO-UDCA microcapsules into Type 1 diabetic animals should provide more insight into the effi cacy and long term eff ects on glycemic control and infl ammation.…”

Hyodeoxycholic acid (HDCA) suppresses intestinal epithelial cell proliferation through FXR‐PI3K/AKT pathway, accompanied by alteration of bile acids metabolism profiles induced by gut bacteria

“…Numerous evidences have demonstrated that secondary BAs are more toxic than their primary counterparts, and may damage the gut and lead to diseases 7,27 . In addition, TUDCA has been reported to exert neutral effect on proliferation of human preadipocytes and adipocytes 42 . Oppositely, TCA has been demonstrated to promote the proliferation of IEC‐6 cells 27 .…”

Bile acids, obesity, and the metabolic syndrome

“…TUDCA reduces adipogenesis in human adipocyte stem cells [46]. Similarly, in another study, UDCA (but not TUDCA) profoundly inhibits adipogenesis, in parallel with activation of extracellular regulated protein kinases 1 and 2 (ERK 1/2) [47]. …”