Glycoursodeoxycholic acid ameliorates diet-induced metabolic disorders with inhibiting endoplasmic reticulum stress

Abstract

Recent studies reveal that bile acid metabolite composition and its metabolism are changed in metabolic disorders, such as obesity, type 2 diabetes and metabolic associated fatty liver disease (MAFLD), yet its role and the mechanism remain largely unknown. In the present study, metabolomic analysis of 163 serum and stool samples of our metabolic disease cohort was performed and we identified glycoursodeoxycholic acid (GUDCA), glycine-conjugated bile acid produced from intestinal bacteria, were decreased in both serum and stool samples from patients with hyperglycemia. RNA-sequencing and quantitative PCR results indicated that GUDCA alleviated endoplasmic reticulum (ER) stress in livers of high fat diet (HFD)-fed mice without alteration of liver metabolism. In vitro, GUDCA reduced palmitic acid induced-ER stress and -apoptosis, as well as stabilized calcium homeostasis. In vivo, GUDCA exerted effects on amelioration of HFD-induced insulin resistance and hepatic steatosis. In parallel, ER stress and apoptosis were decreased in GUDCA-treated mice as compared to vehicle-treated mice in liver. These findings demonstrate that reduced GUDCA is an indicator of hyperglycemia. Supplementation of GUDCA could be an option for the treatment of diet-induced metabolic disorders, including insulin resistance and hepatic steatosis, with inhibiting ER stress.

The promotion of fatty acid β-oxidation by hesperidin via activating SIRT1/PGC1α to improve NAFLD induced by a high-fat diet

“…It has been shown that taurochenodeoxycholic acid (sodium salt) is negatively correlated with PPARγ, 47 which is known to be a major regulator of adipogenesis and insulin resistance, 48 and that changes in the taurochenodeoxycholic acid (sodium salt) content are closely related to PPARγ, affecting adipogenesis and insulin resistance., and our results also showed that HFD affected glucose tolerance and insulin resistance, and could significantly increase the expression of PPARγ (Fig. S3A †); while glycoursodeoxycholic acid could improve HFD-induced insulin resistance and hepatic steatosis, 49 and hypotaurine, a precursor of taurine, promoted fat metabolism and reduces fat accumulation. 50 Further, 9-KODE is a derivative of linoleic acid; while acetoacetate stimulates triacylglycerol synthesis, and these changes in metabolites responding to lipid synthesis and metabolism are consistent with the embodiment of our present findings.…”

Extension Region Domain of Soybean 7S Globulin Contributes to Serum Triglyceride‐Lowering Effect via Modulation of Bile Acids Homeostasis

“…[ 41 ] GUDCA was also confirmed to be decreased in both serum and fecal samples in patients with hyperglycemia, and supplementation of GUDCA can ameliorate HFD‐induced insulin resistance and hepatic steatosis. [ 45 ] Hence, we proposed that the TG‐lowering effect of ER peptides can attribute to modulation of BA signaling by these peptides. In order to validate this hypothesis, we further measured the BAs profiling in feces.…”

Dietary Choline Mitigates High-Fat Diet-Impaired Chylomicrons Assembly via UPRer Modulated by perk DNA Methylation

“…Naturally, as a conserved adaptive mechanism in response to ER dysfunction, ER-unfolded protein response (UPRer) has been found to be involved in the regulation of CMs assembly [ 13 , 16 ], although the relevant mechanism remains unresolved. Meanwhile, multiple investigators suggested HFD is the most common inducement to UPRer [ 17 , 18 ], as seen in our previous study in fish [ 19 ]. However, few studies regarding the mechanism behind HFD-induced UPRer impairing CMs assembly and secretion have been reported.…”