Specific inhibition of bile acid transport alters plasma lipids and GLP-1 (original) (raw)
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Modulation of Bile Acid Metabolism to Improve Plasma Lipid and Lipoprotein Profiles
Journal of Clinical Medicine
New drugs targeting bile acid metabolism are currently being evaluated in clinical studies for their potential to treat cholestatic liver diseases, non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). Changes in bile acid metabolism, however, translate into an alteration of plasma cholesterol and triglyceride concentrations, which may also affect cardiovascular outcomes in such patients. This review attempts to gain insight into this matter and improve our understanding of the interactions between bile acid and lipid metabolism. Bile acid sequestrants (BAS), which bind bile acids in the intestine and promote their faecal excretion, have long been used in the clinic to reduce LDL cholesterol and, thereby, atherosclerotic cardiovascular disease (ASCVD) risk. However, BAS modestly but consistently increase plasma triglycerides, which is considered a causal risk factor for ASCVD. Like BAS, inhibitors of the apical sodium-dependent bile acid transporter (AS...
BMJ Open, 2022
To cite: Hatano T, Oyama G, Shimo Y, et al. Investigating the efficacy and safety of elobixibat, an ileal bile acid transporter inhibitor, in patients with Parkinson's disease with chronic constipation: a multicentre, placebo-controlled, randomised, double-blind, parallel-group study (CONST-PD). BMJ Open 2022;12:e054129.
The FASEB Journal, 2002
Reduction of plasma cholesterol by statins is fundamental to prevent coronary heart disease. Such therapy is often sub-optimal, however, particularly in patients with reduced LDL receptors (familial hypercholesterolemia), and novel or adjuvant therapies are therefore warranted. Cholesterol elimination is profoundly influenced by the rate of its conversion to bile acids (BA), regulated by the enzyme Cyp7a1. Induced fecal loss of BA by resin treatment reduces plasma cholesterol, presumably through induction of hepatic LDL receptors (LDLR). We here describe the effect of PR835, a drug belonging to a new class of lipid-lowering agents that inhibit the Slc10a2 protein, the intestinal transporter responsible for active uptake of BA. Treatment reduced plasma cholesterol by 40% in mice devoid of both the LDLR and its ligand, apoE, while triglycerides and HDL cholesterol were unchanged. Cyp7a1 enzyme activity and mRNA were induced several-fold, and hepatic HMG CoA reductase mRNA increased, mirroring an induced synthesis of BA and cholesterol. The addition of a statin potentiated the effect, leading to reductions of plasma total and LDL cholesterol by 64% and 70%, respectively. These effects could not be attributed to induction of other known hepatic lipoprotein receptors and indicate the presence of new points of targeting in lipid-lowering therapy.
Gastroenterology Research and Practice
Backgrounds and Aims. Elobixibat is a bile acid transporter inhibitor indicated for constipation. Previous studies were performed mainly for the nonelderly and were biased to female. We analyzed the efficacy of elobixibat also for the elderly and male. Materials and Methods. This was a multicenter retrospective cohort study. The subjects were patients aged ≥20 years treated for chronic constipation from May 2018 to November 2019 at 12 related institutions. Patients were divided into ≤74 years and ≥75 years old. Elobixibat at 10 mg/day was prescribed for two weeks. We then analyzed the discontinuation due to ineffectiveness, change of spontaneous bowel movements (SBM), stool consistency, the time until the first SBM, adverse events, and effect-related factors. Results. There were 140 cases (61 males) evaluated, with an average age of 72.1±13.6 years (≤74 years: 71 cases; ≥75 years: 69 cases). The discontinuation rate was 7.9%. The SBM (times/week) increased from 2.86 to 6.08 (p<0....
We investigated the effect of ileal bile acid transport on the regulation of classic and alternative bile acid synthesis in cholesterol-fed rats and rabbits. Bile acid pool sizes, fecal bile acid outputs (synthesis rates), and the activities of cholesterol 7 ␣ -hydroxylase (classic bile acid synthesis) and cholesterol 27-hydroxylase (alternative bile acid synthesis) were related to ileal bile acid transporter expression (ileal apical sodium-dependent bile acid transporter, ASBT). Plasma cholesterol levels rose 2.1-times in rats (98 ؎ 19 mg/dl) and 31-times (986 ؎ 188 mg/dl) in rabbits. The bile acid pool size remained constant (55 Ϯ 17 mg vs. 61 ؎ 18 mg) in rats but doubled (254 ؎ 46 to 533 ؎ 53 mg) in rabbits. ASBT protein expression did not change in rats but rose 31% ( P Ͻ 0.05) in rabbits. Fecal bile acid outputs that reflected bile acid synthesis increased 2-and 2.4-times ( P Ͻ 0.05) in cholesterol-fed rats and rabbits, respectively. Cholesterol 7 ␣ -hydroxylase activity rose 33% (24 ؎ 2.4 vs. 18 ؎ 1.6 pmol/mg/min, P Ͻ 0.01) and mRNA levels increased 50% ( P Ͻ 0.01) in rats but decreased 68% and 79%, respectively, in cholesterol-fed rabbits. Cholesterol 27-hydroxylase activity remained unchanged in rats but rose 62% ( P Ͻ 0.05) in rabbits. Classic bile acid synthesis (cholesterol 7 ␣hydroxylase) was inhibited in rabbits because an enlarged bile acid pool developed from enhanced ileal bile acid transport. In contrast, in rats, cholesterol 7 ␣ -hydroxylase was stimulated but the bile acid pool did not enlarge because ASBT did not change.
Diabetologia, 2012
Aims/hypothesis The primary aim of this completed multicentre randomised, parallel, double-blind placebo-controlled study was to elucidate the mechanisms of glucose-lowering with colesevelam and secondarily to investigate its effects on lipid metabolism (hepatic de novo lipogenesis, cholesterol and bile acid synthesis). Methods Participants with type 2 diabetes (HbA 1c 6.7-10.0% [50-86 mmol/mol], fasting glucose <16.7 mmol/l, fasting triacylglycerols <3.9 mmol/l and LDL-cholesterol >1.55 mmol/l) treated with diet and exercise, sulfonylurea, metformin or a combination thereof, were randomised by a central coordinator to either 3.75 g/day colesevelam (n=30) or placebo (n=30) for 12 weeks at three clinical sites in the USA. The primary measure was the change from baseline in glucose kinetics with colesevelam compared to placebo treatment. Fasting and postprandial glucose, lipid and bile acid pathways were measured at baseline and post-treatment using stable isotope techniques. Plasma glucose, insulin, total glucagon-like peptide-1 (GLP-1), total glucose-dependent insulinotropic polypeptide (GIP), glucagon and fibroblast growth factor-19 (FGF-19) concentrations were measured during the fasting state and following a meal tolerance test. Data was collected by people blinded to treatment. Results Compared with placebo, colesevelam improved HbA 1c (mean change from baseline of 0.3 [SD 1.1]% for placebo [n=28] and −0.3 [1.1]% for colesevelam [n=26]), glucose concentrations, fasting plasma glucose clearance and glycolytic disposal of oral glucose. Colesevelam did not affect gluconeogenesis or appearance rate (absorption) of oral glucose. Fasting endogenous glucose production and glycogenolysis significantly increased with placebo but were unchanged with colesevelam (treatment effect did not reach statistical significance). Compared with placebo, colesevelam increased total GLP-1 and GIP concentrations and improved HOMA-beta cell function while insulin, glucagon and HOMA-insulin resistance were unchanged. Colesevelam increased cholesterol and bile acid synthesis and decreased FGF-19 concentrations. However, no effect was seen on fractional hepatic de novo lipogenesis. Conclusions/interpretation Colesevelam, a non-absorbed bile acid sequestrant, increased circulating incretins and improved tissue glucose metabolism in both the fasting and postprandial states in a manner different from other approved oral agents.
Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association, 2017
Short-term administration of delayed-release chenodeoxycholic acid to patients with irritable bowel syndrome with constipation (IBS-C) accelerates colonic transit and reduces symptoms. A preliminary study has shown that patients with IBS-C have reduced levels of bile acids (BAs) in feces and reduced synthesis of BA. We compared the levels of primary and secondary BAs in fecal samples collected over a 48-hour period from patients with IBS-C on a diet that contained 100 g fat per day, and compared them with levels in samples from healthy volunteers (controls). We also examined the relationship between overall colonic transit and biomarkers of BAs in patients with IBS-C. We performed a retrospective study of 45 patients with IBS-C and 184 controls. For controls, we estimated the 10th percentile of fasting serum levels of 7α-hydroxy-4-cholesten-3-one (C4, n = 184) and 48-hour fecal BAs (n = 46), and the 90th percentile of the fasting serum level of fibroblast growth factor 19 (FGF19, n ...
Journal of Functional Foods, 2019
In this study, under dyslipidemia (D) and dyslipidemia with diabetes (DD) conditions, we assessed the intestinal bile acid (BA) uptake, BA transporter expression and de novo BA synthesis in rats. The restorative potentials n-3 fatty acids [{α-linolenic acid (ALA), DD + canola oil (CNO)} and eicosapentaenoic acid (EPA) + docosahexaenoic acid (DHA), DD + fish oil (FO)}] were also assessed. DD group had significantly (p < 0.05) increased intestinal BA uptake and Asbt and Osta/b mRNA expression, increased serum BA level, decreased hepatic Ntcp, Bsep and Cyp7a1 mRNA expression, increased hepatic HMG-CoA reductase activity, increased hepatic Fxr and Shp mRNA expression, decreased hepatic Lrh-1 and Hnf4a mRNA expression and decreased fecal BA level, when compared to control, D, DD + CNO, and DD + FO group. Our data show for the first time that, hyperglycemia exacerbates dyslipidemia-induced dysregulation of BA metabolism and transport. Dietary EPA + DHA exhibited superior effect than ALA in normalizing dyslipidemia and hyperglycemia-induced disturbances.
Atherosclerosis, 2003
Male Hartley guinea pigs were randomly allocated to one of four treatments, 10 guinea pigs per group, for 12 weeks. The control diet contained no ASBT inhibitor (ASBTi) or simvastatin. Low ASBTi (LowASBTi) and high ASBTi (HighASBTi) were monotherapies containing 0.03 g/100 g and 0.1 g/100 g of the ASBTi SC-435. Combination therapy (COMBO) was a combination therapy consisting of 0.03 g/100 g ASBTi and 0.05 g/100 g simvastatin. Based on food consumption, guinea pigs received 17.2 and 47.8 mg/kg per day ASBTi in the ASBTi groups or 13.7 mg/kg per day ASBTi and 21.4 mg/kg per day simvastatin in the COMBO group. The amount of cholesterol in each diet was 0.25 g/100 g. LDL cholesterol was 40 and 70% lower with the HighASBTi and COMBO treatments compared to controls. Plasma triglycerides (TG) were 70% lower with COMBO therapy while HDL cholesterol was 43-47% higher with all treatments. Hepatic free cholesterol was reduced 60-80% with all treatments. Cholesterol content in the aortic arch was reduced by 25 and 42% in the HighASBTi and COMBO groups. Fecal bile acids were increased by 2.5-and 4-fold with HighASBTi and COMBO treatments. These data suggest that the interruption in the enterohepatic circulation of bile acids by ASBTi and statin co-administration therapy cause a significant reduction in plasma cholesterol concentrations and attenuate the progression of atherosclerosis in guinea pigs.
Science translational medicine, 2016
Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the Western world, and safe and effective therapies are needed. Bile acids (BAs) and their receptors [including the nuclear receptor for BAs, farnesoid X receptor (FXR)] play integral roles in regulating whole-body metabolism and hepatic lipid homeostasis. We hypothesized that interruption of the enterohepatic BA circulation using a luminally restricted apical sodium-dependent BA transporter (ASBT) inhibitor (ASBTi; SC-435) would modify signaling in the gut-liver axis and reduce steatohepatitis in high-fat diet (HFD)-fed mice. Administration of this ASBTi increased fecal BA excretion and messenger RNA (mRNA) expression of BA synthesis genes in liver and reduced mRNA expression of ileal BA-responsive genes, including the negative feedback regulator of BA synthesis, fibroblast growth factor 15. ASBT inhibition resulted in a marked shift in hepatic BA composition, with a reduction in hydrophilic, FXR a...