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Inhibiting Insulin Resistance and Accumulation of Triglycerides and Cholesterol in the Liver
Published in Christophe Wiart, Medicinal Plants in Asia for Metabolic Syndrome, 2017
Bile acids in the liver activate a nuclear receptor termed farnesoid X receptor that controls triglyceride and cholesterol metabolism. With regard to cholesterol metabolism, this nuclear receptor induces the expression of small heterodimer partner (SHP) that inhibits CYP7A1, an enzyme also known as cholesterol-7α-hydroxylase, which catalyze the synthesis of bile acids from cholesterol.35 Besides, activation of farnesoid X receptor prompts the secretion of bile acids and cholesterol into bile duct via the activation of hepatic ATP-binding cassette (ABC) transporters ABCB11 and ABCG5/8, respectively.36 Natural products with the ability to activate farnesoid X receptor promote biliary cholesterol secretion and reduces fractional absorption of dietary cholesterol.37 The roots of Lindera strychnifolia (Sieb. et Zucc.) Fern.-Vill. contain isoquinoline alkaloids including boldine (Figure 3.3).38 Boldine given orally at a dose of 100 mg/kg/day for 8 weeks reduced the glycaemia of rodents poisoned with streptozotocin from 538.4 to 311.4 mg/dL, increased body weight, reduced hepatic lipid peroxidation, and increased hepatic glutathione peroxidase activity.39 Boldine is antioxidant as at a concentration of 100 µM prevented in vitro the generation of superoxide and hydrogen peroxide production from hepatic mitochondria challenged with antimycin.39 In a subsequent study, boldine given to hereditary hypertriglyceridemic rats on as part of 0.2% of high-sucrose diet for 6 weeks induced a decrease of glycaemia from 15 to 14 mmol/L, increased high-density lipoprotein–cholesterol from 0.8 to 0.9 mmol/L, triglycerides from 2.7 to 1.5 mmol/L, and bile acids from 5.5 to 2.7 µmol/L, whereas plasma cholesterol was unchanged.40 This alkaloid reduced hepatic triglyceride contents in high-sucrose diet rats from 4.9 to 4.2 µmol/L and improved hepatic cytoarchitecture.40 Boldine increased bile flow and bile acid secretion toward levels seen in control animals, increased hepatic glutathione contents, and increased the expression of transporters for bile acids, ATP-dependent human bile salt export pump (Bsep/ABCB11) and sodium-taurocholate cotransporting polypeptide (Ntcp).40 Boldine at a concentration of 5 µM evoked the activation of farnesoid X receptor in transfected HepG2 cells.41 Other hepatoprotective constituents in the roots of Lindera strychnifolia (Sieb. et Zucc.) Fern.-Vill. are sesquiterpenes of which bi-linderone and lindestrene.38 Lindestrene given orally at a dose of 100 mg/kg, twice daily for 3 days, and 1 hour before galactosamine-induced hepatic insults evoked a decrease of plasmatic aspartate aminotransferase and GPT I Wistar rats.42 Bi-linderone at a concentration of 1 µg/mL protected HepG2 cells against glucosamine-induced inhibition of insulin receptor sensitivity as evidenced by increased expression of phosphorylated insulin receptor and phosphorylated Akt.43
The relationship between bile acids levels and the prognosis of patients with diabetes on maintenance hemodialysis: a retrospective study
Published in Renal Failure, 2023
Bin Li, Cong Peng, Yili Wang, Rong Ma, Ya Feng
Additionally, BAs may have a direct cardiovascular benefit. Hu et al. [32] revealed that INT-777 attenuated the neuroinflammation mediated by NLRP3-ASC inflammatory bodies through the TGR5/cAMP/PKA signaling pathway after the occurrence of subarachnoid hemorrhage in rats. Activating the TGR5 signaling pathway can reduce inflammation and improve post-infarction cardiac function. Strategies to control BAs metabolism and TGR5 signaling to improve the inflammatory response may benefit patients with myocardial infarction. Moreover, Farnesoid X receptor (FXR) activation was also found to have a similar effect. The FXR signaling pathway is an attractive therapeutic target for treating atherosclerosis [33]. Mesenchymal stromal cells overexpressing FXR play a cardioprotective role in acute ischemic heart injury by binding endogenous BAs [34].
Kidney and lipids: novel potential therapeutic targets for dyslipidemia in kidney disease?
Published in Expert Opinion on Therapeutic Targets, 2022
Konrad Zuzda, Wiktoria Grycuk, Jacek Małyszko, Jolanta Małyszko
In another model of diabetic DBA/2 J and db/db mice, Wang et al. [178] reported that the nuclear hormone receptor farnesoid X receptor (FXR) and G protein–coupled receptor TGR5 have renoprotective roles in diabetes- and obesity-related kidney diseases. Administration of the dual FXR/TGR5 agonist INT-767 improved proteinuria and prevented podocyte injury, mesangial expansion, and tubulointerstitial fibrosis. This agent affects multiple pathways, including stimulation of a signaling cascade involving AMP-activated protein kinase, sirtuin 1, PGC-1α (peroxisome proliferator-activated receptor-gamma coactivator), sirtuin 3, estrogen-related receptor-α, and Nrf-1, inhibition of endoplasmic reticulum stress, and inhibition of enhanced renal fatty acid and cholesterol metabolism. In addition, in mice with diet-induced obesity, a dual FXR/TGR5 agonist prevents mitochondrial dysfunction, oxidative stress, and kidney fibrosis. The authors suggested that INT-767 could be a promising agent for the treatment of renal complications in diabetes and obesity. As angiotensin II exacerbates mitochondrial reactive oxygen species synthesis and mitochondrial fragmentation in podocytes, both in vivo and in vitro, Zhu et al. [179] recently showed that mitoquinone, a mitochondria-targeted antioxidant, can reverse injury caused by angiotensin II.
Emerging therapies in the management of Irritable Bowel Syndrome (IBS)
Published in Expert Opinion on Emerging Drugs, 2022
Jill E. Elwing, Hadi Atassi, Benjamin D. Rogers, Gregory S. Sayuk
Perhaps as many as 1 in 3 patients with IBS-D or functional diarrhea have evidence of increased excretion of bile acids (BAs) in the stool, or serologic markers evidencing upregulation of bile acid synthesis [74]. The presence of bile acids in the gut leads to increased fluid secretion in the colon and enhances colonic contractions [56]. These observations have led to a pursuit of pharmacotherapeutics which to bind bile acids (‘bile acid sequestrants’) or down regulate production through agonism of the nuclear farnesoid X receptor (FXR) [75]. FXR agonists increase transcription of fibroblast growth factor 19 (FGF-19), an endocrine hormone that provides negative feedback on BA production via inhibition of rate-limiting enzymes in hepatic synthesis of primary BAs. Additionally, FGF-19 analogs are currently under study [76]. In the opposite spectrum, a considerable portion of IBS-C patients have been found to have deficiencies in colonic bile acids. This has led to an interest in developing inhibitors of ileal BA uptake, such as elobixibat [77].