Dual Activation of the Bile Acid Nuclear Receptor FXR and G-Protein-Coupled Receptor TGR5 Protects Mice against Atherosclerosis

Edelstein

Gafter

et al. 2015

JASN

Self Cite

150

Obesity and diabetes mellitus are the leading causes of renal disease. In this study, we determined the regulation and role of the G protein-coupled bile acid receptor TGR5, previously shown to be regulated by high glucose and/or fatty acids, in obesity-related glomerulopathy (ORG) and diabetic nephropathy (DN). Treatment of diabetic db/db mice with the selective TGR5 agonist INT-777 decreased proteinuria, podocyte injury, mesangial expansion, fibrosis, and CD68 macrophage infiltration in the kidney. INT-777 also induced renal expression of master regulators of mitochondrial biogenesis, inhibitors of oxidative stress, and inducers of fatty acid b-oxidation, including sirtuin 1 (SIRT1), sirtuin 3 (SIRT3), and Nrf-1. Increased activity of SIRT3 was evidenced by normalization of the increased acetylation of mitochondrial superoxide dismutase 2 (SOD2) and isocitrate dehydrogenase 2 (IDH2) observed in untreated db/db mice. Accordingly, INT-777 decreased mitochondrial H 2 O 2 generation and increased the activity of SOD2, which associated with decreased urinary levels of H 2 O 2 and thiobarbituric acid reactive substances. Furthermore, INT-777 decreased renal lipid accumulation. INT-777 also prevented kidney disease in mice with dietinduced obesity. In human podocytes cultured with high glucose, INT-777 induced mitochondrial biogenesis, decreased oxidative stress, and increased fatty acid b-oxidation. Compared with normal kidney biopsy specimens, kidney specimens from patients with established ORG or DN expressed significantly less TGR5 mRNA, and levels inversely correlated with disease progression. Our results indicate that TGR5 activation induces mitochondrial biogenesis and prevents renal oxidative stress and lipid accumulation, establishing a role for TGR5 in inhibiting kidney disease in obesity and diabetes.

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

G Protein-Coupled Bile Acid Receptor TGR5 Activation Inhibits Kidney Disease in Obesity and Diabetes

Edelstein

Gafter

et al. 2015

JASN

Self Cite

150

Journal of Clinical Investigation

“…Calcified lesions at the aortic valve were analyzed as previously described (6,9,18,65). Apoptotic cells and CHOP in aortic sinuses were detected using an In Situ Cell Death Detection Kit (Roche Diagnostics) and a CHOP monoclonal antibody (Cell Signaling Technology), respectively, as previously described (6,9,49 Biochemical analysis.…”

Section: Discussionmentioning

confidence: 99%

Saturated phosphatidic acids mediate saturated fatty acid–induced vascular calcification and lipotoxicity

Masuda¹,

Miyazaki–Anzai²,

Keenan³

et al. 2015

Self Cite

R e s e a R c h a R t i c l e 4 5 4 4jci.org Volume 125 Number 12 December 2015 IntroductionVascular calcification is a major complication in patients who are aging, have diabetes, or have chronic kidney disease (CKD) and is an active process that differentiates vascular smooth muscle cells (VSMCs) into osteoblast-like cells (1, 2). This process is highly regulated by transcription factors involved in osteogenic differentiation, such as RUNX2, MSX2, and ATF4 (3-5). Several in vitro and in vivo studies have shown lipids to play a causative role in the pathogenesis of vascular calcification in addition to inorganic phosphate, inflammatory cytokines, and oxidative stress (6-13). Treatment with unsaturated fatty acids (UFAs) inhibits vascular mineralization and osteogenic differentiation (14, 15), whereas oxidized lipids, such as oxysterols and oxidized phospholipids, elicit procalcific effects in vascular cells (9,16,17). In addition to this evidence, we also previously reported that saturated fatty acids (SFAs) and calcium simultaneously accumulate during osteogenic differentiation of vascular cells (18,19). Ectopic accumulation of excess lipids, called lipotoxicity, plays a central role in the pathogenesis of cardio-metabolic diseases, including diabetes, obesity, atherosclerosis, and vascular calcification (20-24). However, evidence from a number of experimental systems is emerging, stating that SFAs and UFAs have distinct contributions to lipotoxicity (25,26). SFAs such as palmitic acid (16:0) and stearic acid (18:0) induce apoptosis, oxidative stress, and ER stress in a variety of mammalian cell lines (including hepatocytes, macrophages, and VSMCs), whereas UFAs such as oleic acid have no or minimal lipotoxic properties (5,(25)(26)(27)(28)(29)(30). In addition, cotreatment with UFAs blocks SFA-mediated lipotoxic effects (25,29). However, the specific metabolite of SFAs that induces lipotoxicity, the mechanism underlying SFA-mediated lipotoxicity, and how UFAs block SFA-mediated lipotoxicity are largely unknown.Proper intracellular SFA and UFA balance is controlled by a lipogenic enzyme called stearoyl-CoA desaturase (SCD) (31,32). SCD catalyzes the conversion of SFAs to monounsaturated FAs, mainly 16:0 into palmitoleate (16:1n-7), and 18:0 into oleate (18:1n-9) (33,34). This introduction of a double bond markedly impacts several chemical properties, including a decrease in melting point and an increase in solubility. The activation of SCD therefore neutralizes SFA-mediated lipotoxicity (5, 25). The expression of SCD is highly regulated by a number of hormonal and dietary factors (33,(35)(36)(37). Recently, we found that the accumulation of SFAs by either supplementation with exogenous SFAs or inhibition of SCD induces mineralization of VSMCs (5,19). In addition, SFA-mediated lipotoxicity and vascular calcification were completely blocked by an acyl-CoA synthetase inhibitor and were attenuated by the shRNA-mediated inhibition of fatty acid elongase-6 (Elovl6) (5), suggesting that stearoyl-CoA (18:0-CoA) or its ...

“…INT-767 shows efficient intestinal absorption and its biliary excretion is facilitated by 3-glucuronididation (25 (26). INT-767 has also marked anti-inflammatory (27), anti-atherosclerotic (28), and anticholestatic effects (29).…”

Section: Fxr-tgr5 Reverses Age-related Kidney Diseasementioning

confidence: 99%

A dual agonist of farnesoid X receptor (FXR) and the G protein–coupled receptor TGR5, INT-767, reverses age-related kidney disease in mice

Luo

Journal of Biological Chemistry

et al. 2017

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Even in healthy individuals, renal function gradually declines during aging. However, an observed variation in the rate of this decline has raised the possibility of slowing or delaying age-related kidney disease. One of the most successful interventional measures that slows down and delays age-related kidney disease is caloric restriction. We undertook the present studies to search for potential factors that are regulated by caloric restriction and act as caloric restriction mimetics. Based on our prior studies with the bile acid-activated nuclear hormone receptor farnesoid X receptor (FXR) and G protein coupled membrane receptor TGR5 that demonstrated beneficial effects of FXR and TGR5 activation in the kidney, we reasoned that FXR and TGR5 could be excellent candidates. We therefore determined the effects of aging and caloric restriction on the expression of FXR and TGR5 in the kidney. We found that FXR and TGR5 expression are decreased in the aging kidney, and that caloric restriction prevents these age-related decreases. Interestingly, in long-lived Ames dwarf mice renal FXR and TGR5 expression levels were also increased. A 2-month treatment of 22-month-old C57BL/6J mice with the FXR-TGR5 dual agonist induced caloric restriction-like effects and reversed age-related increases in proteinuria, podocyte injury, fibronectin accumulation, TGF-β expression, and, most notably, age-related impairments in mitochondrial biogenesis and mitochondrial function. Furthermore, in podocytes cultured in serum obtained from old mice, INT-767 prevented the increases in the proinflammatory markers TNF-α, toll-like receptor 2 (TLR2), and TLR4. In summary, our results indicate that FXR and TGR5 may play an important role in modulation of age-related kidney disease.