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Metabolomics and lipidomics in NAFLD: biomarkers and non-invasive diagnostic tests.
Masoodi, M, Gastaldelli, A, Hyötyläinen, T, Arretxe, E, Alonso, C, Gaggini, M, Brosnan, J, Anstee, QM, Millet, O, Ortiz, P, et al
Nature reviews. Gastroenterology & hepatology. 2021;(12):835-856
Abstract
Nonalcoholic fatty liver disease (NAFLD) is one of the most common liver diseases worldwide and is often associated with aspects of metabolic syndrome. Despite its prevalence and the importance of early diagnosis, there is a lack of robustly validated biomarkers for diagnosis, prognosis and monitoring of disease progression in response to a given treatment. In this Review, we provide an overview of the contribution of metabolomics and lipidomics in clinical studies to identify biomarkers associated with NAFLD and nonalcoholic steatohepatitis (NASH). In addition, we highlight the key metabolic pathways in NAFLD and NASH that have been identified by metabolomics and lipidomics approaches and could potentially be used as biomarkers for non-invasive diagnostic tests. Overall, the studies demonstrated alterations in amino acid metabolism and several aspects of lipid metabolism including circulating fatty acids, triglycerides, phospholipids and bile acids. Although we report several studies that identified potential biomarkers, few have been validated.
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Bile acids mediated potential functional interaction between FXR and FATP5 in the regulation of Lipid Metabolism.
Kumari, A, Pal Pathak, D, Asthana, S
International journal of biological sciences. 2020;(13):2308-2322
Abstract
Perturbation in lipid homeostasis is one of the major bottlenecks in metabolic diseases, especially Non-alcoholic Fatty Liver Disease (NAFLD), which has emerged as a leading global cause of chronic liver disease. The bile acids (BAs) and their derivatives exert a variety of metabolic effects through complex and intertwined pathways, thus becoming the attractive target for metabolic syndrome treatment. To modulate the lipid homeostasis, the role of BAs, turn out to be paramount as it is essential for the absorption, transport of dietary lipids, regulation of metabolic enzymes and transporters that are essential for lipid modulation, flux, and excretion. The synthesis and transport of BAs (conjugated and unconjugated) is chiefly controlled by nuclear receptors and the uptake of long-chain fatty acids (LCFA) and BA conjugation via transporters. Among them, from in-vivo studies, farnesoid X receptor (FXR) and liver-specific fatty acid transport protein 5 (FATP5) have shown convincing evidence for their key roles in lipid homeostasis and reversal of fatty liver disease substantially. BAs have a wider range of biological effects as they are identified as modulators for FXR and FATP5 both and therefore hold a significant promise for altering the lipid content in the treatment of a metabolic disorder. BAs also have received noteworthy interest in drug delivery research due to its peculiar physicochemical properties and biocompatibility. Here, we are highlighting the connecting possibility of BAs as an agonist for FXR and antagonist for FATP5, paving an avenue to target them for designing synthetic small molecules for lipid homeostasis.
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Interaction of gut microbiota with bile acid metabolism and its influence on disease states.
Staley, C, Weingarden, AR, Khoruts, A, Sadowsky, MJ
Applied microbiology and biotechnology. 2017;(1):47-64
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Abstract
Primary bile acids serve important roles in cholesterol metabolism, lipid digestion, host-microbe interactions, and regulatory pathways in the human host. While most bile acids are reabsorbed and recycled via enterohepatic cycling, ∼5% serve as substrates for bacterial biotransformation in the colon. Enzymes involved in various transformations have been characterized from cultured gut bacteria and reveal taxa-specific distribution. More recently, bioinformatic approaches have revealed greater diversity in isoforms of these enzymes, and the microbial species in which they are found. Thus, the functional roles played by the bile acid-transforming gut microbiota and the distribution of resulting secondary bile acids, in the bile acid pool, may be profoundly affected by microbial community structure and function. Bile acids and the composition of the bile acid pool have historically been hypothesized to be associated with several disease states, including recurrent Clostridium difficile infection, inflammatory bowel diseases, metabolic syndrome, and several cancers. Recently, however, emphasis has been placed on how microbial communities in the dysbiotic gut may alter the bile acid pool to potentially cause or mitigate disease onset. This review highlights the current understanding of the interactions between the gut microbial community, bile acid biotransformation, and disease states, and addresses future directions to better understand these complex associations.
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The role of bile acids in the pathogenesis of bowel diseases.
Panek-Jeziorna, M, Mulak, A
Postepy higieny i medycyny doswiadczalnej (Online). 2017;(1):737-746
Abstract
Bile acids not only play a cardinal role in the digestion and absorption of fat and fat-soluble vitamins, but also significantly affect gastrointestinal motor, sensory and secretory functions, intestinal barrier permeability and the regulation of the inflammatory response. The results of recent studies have revealed complex interactions between bile acids and the gut microbiota. In addition, bile acids also play a role of signaling molecules regulating the activity of lipid and glucose metabolic pathways, as well as a role of ligands for transcription factors. Genetic factors associated with the regulation of bile acid synthesis, transport and action may significantly influence gastrointestinal function and predispose to diarrhea resulting from bile acid malabsorption. Methods used in the diagnosis of bile acid malabsorption include 75selenium-homotaurocholic acid test, serum C4 and fibroblast growth factor 19 (FGF19), as well as fecal bile acid levels. The paper presents the latest data on the role of bile acid in the pathogenesis of irritable bowel syndrome, inflammatory bowel diseases and colorectal cancer. Advances in the treatment of disturbances in bile acids absorption and synthesis are also presented. A better understanding of molecular mechanisms regulating bile acid action may have implication for colorectal cancer prevention.
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Serum bile acids and GLP-1 decrease following telemetric induced weight loss: results of a randomized controlled trial.
Biemann, R, Penner, M, Borucki, K, Westphal, S, Luley, C, Rönicke, R, Biemann, K, Weikert, C, Lux, A, Goncharenko, N, et al
Scientific reports. 2016;:30173
Abstract
Bile acids (BAs) are increasingly recognised as metabolic regulators, potentially improving insulin sensitivity following bariatric surgery. However, physiological relevance of such observations remains unknown. Hence, we analysed serum BA composition and associated gut-derived hormone levels following lifestyle-induced weight loss in individuals with metabolic syndrome (MetS). 74 non-smoking men (45-55 yr) with MetS were randomised to a lifestyle-induced weight loss program (supervision via telemonitoring) or to a control arm. Before and after a 6 months intervention period clinical and laboratory parameters, body composition, serum BA profile, FGF-19, and GLP-1 concentrations were determined in fasting blood samples. 30 participants in the control and 33 participants in the treatment arm completed the study and were included in the data analysis. In participants of the treatment arm lifestyle-induced weight loss resulted in markedly improved insulin sensitivity. Serum levels of BA species and total GLP-1 decreased, while FGF-19 remained stable. Serum BA composition changed towards an increased 12α-hydroxylated/non-12α-hydroxylated ratio. None of these parameters changed in participants of the control arm. Our results demonstrate that improved metabolic control by lifestyle modifications lowers serum levels of BAs and GLP-1 and changes serum BA composition towards an increased 12α/non-12α ratio (ICTRP Trial Number: U1111-1158-3672).
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Gut permeability, its interaction with gut microflora and effects on metabolic health are mediated by the lymphatics system, liver and bile acid.
Tran, CD, Grice, DM, Wade, B, Kerr, CA, Bauer, DC, Li, D, Hannan, GN
Future microbiology. 2015;(8):1339-53
Abstract
There is evidence to link obesity (and metabolic syndrome) with alterations in gut permeability and microbiota. The underlying mechanisms have been questioned and have prompted this review. We propose that the gut barrier function is a primary driver in maintaining metabolic health with poor health being linked to 'gut leakiness'. This review will highlight changes in intestinal permeability and how it may change gut microflora and subsequently affect metabolic health by influencing the functioning of major bodily organs/organ systems: the lymphatic system, liver and pancreas. We also discuss the likelihood that metabolic syndrome undergoes a cyclic worsening facilitated by an increase in intestinal permeability leading to gut dysbiosis, culminating in ongoing poor health leading to further exacerbated gut leakiness.
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Specific inhibition of bile acid transport alters plasma lipids and GLP-1.
Rudling, M, Camilleri, M, Graffner, H, Holst, JJ, Rikner, L
BMC cardiovascular disorders. 2015;:75
Abstract
BACKGROUND Elobixibat is a minimally absorbed ileal bile acid (BA) transporter (IBAT) inhibitor in development against chronic constipation (CC) and constipation-predominant Irritable Bowel Syndrome (IBS-C). CC is associated with an increased risk for cardiovascular disease and type2 diabetes mellitus. The objectives of this study were to evaluate metabolic effects of elobixibat. Effects on plasma lipids and BA synthesis were evaluated utilizing a 4-week, placebo-controlled study in patients with dyslipidemia while changes of glucagon-like peptide-1 (GLP-1) by elobixibat was assayed in samples from a 14 day high-dose elobixibat study in patients with CC. METHODS Thirty-six dyslipidemic patients, 21 females, mean age 63 years, were randomized to 2.5 mg or 5 mg elobixibat or placebo once daily for four weeks. The primary endpoint was the change in low density lipoprotein (LDL) cholesterol. Secondary endpoints included other lipid parameters and serum 7α-hydroxy-4-cholesten-3-one (C4), a marker of BA (bile acid) synthesis. Another study, in 36 patients with CC treated with high dose elobixibat; 15 mg or 20 mg/day or placebo for 14 days, was evaluated for changes in GLP-1. RESULTS In the dyslipidemia study LDL cholesterol was reduced by 7.4 % (p = 0.044), and the LDL/HDL ratio was decreased by 18 % (p = 0.004). Serum C4 increased, indicating that BA synthesis was induced. No serious adverse events were recorded. In the CC study, GLP-1 increased significantly in both the 15 mg (20.7 ± 2.4 pmol/L; p = 0.03) and the 20 mg group (25.6 ± 4.9 pmol/L; p = 0.02). CONCLUSIONS Elobixibat reduces LDL cholesterol and LDL/HDL ratio and increase circulating peak GLP-1 levels, the latter in line with increased intestinal BA mediated responses in humans. TRIAL REGISTRATIONS ClinicalTrial.gov: NCT01069783 and NCT01038687 .
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The role of bile acid sequestrants in the management of type 2 diabetes mellitus.
Ganda, OP
Metabolic syndrome and related disorders. 2010;(Suppl 1):S15-21
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Abstract
The prevalence of type 2 diabetes (T2DM) and cardiovascular disease (CVD) continues to escalate globally. There is now abundant clinical trial evidence that the optimal treatment of CVD risk factors, with lifestyle changes aimed at weight loss in most patients, and pharmacologic management of dyslipidemia and hyperglycemia, can help mitigate the CVD burden. Yet more than 50% of patients are still not achieving glycosylated hemoglobin (HbA1c) and low-density lipoprotein cholesterol (LDL-C) goals. Over the past 15 years, many novel and emerging drugs have made it possible to achieve optimal glycemic control, generally in combination therapy, without untoward effects of weight gain, hypoglycemia, and other adverse effects with traditional agents. Although the long-term efficacy and safety of some of the newer classes of agents are yet to be determined, bile acid sequestrants represent a unique long-standing class of agents. These drugs have the dual efficacy in glycemic control and LDL-C reduction, and an established record of long-term safety. Colesevelam HCl is the only drug approved for this dual indication and is an adjunct in the treatment of both hyperglycemia and hypercholesterolemia that frequently co-exist in adults with T2DM.
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Beyond cholesterol lowering: pleiotropic effects of bile acid binding resins against cardiovascular disease risk factors in patients with metabolic syndrome.
Yamaoka-Tojo, M, Tojo, T, Izumi, T
Current vascular pharmacology. 2008;(4):271-81
Abstract
Prospective epidemiologic studies have shown that dyslipidemia and hyperglycemia are major risk factors for atherosclerotic cardiovascular diseases. Undesirable metabolic conditions are observed to coexist in patients with metabolic syndrome, which is an important risk factor for cardiovascular disease. To prevent cardiovascular disease, a pleiotropic agent is needed to improve the metabolic disorder in patients with metabolic syndrome. Bile acid binding resins increase the fecal excretion of bile acids. The decrease in bile acids returned to the liver leads to an up-regulation of hepatic low-density lipoprotein (LDL) receptor activity, which decreases LDL cholesterol (LDL-C) in the circulation and increases high-density lipoprotein cholesterol. On the other hand, bile acids can also regulate the transcription of genes involved in LDL-C synthesis and cholesterol homeostasis via nuclear hormone receptors. Consequently, these receptors may represent novel therapeutic targets for dyslipidemia and provide insight into the role of the bile acid pathway in other metabolic processes. This review focuses on the recent findings on bile acid binding resins and cardiovascular disease risk factors. Moreover, known and proposed mechanisms of how bile acid binding resins may improve glucose and energy metabolism are discussed; these effects may help to explain the mechanisms by which bile acid binding resins may reduce cardiovascular disease.