Modulation of Bile Acid Metabolism to Improve Plasma Lipid and Lipoprotein Profiles

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 (ASBTi’s) reduce intestinal bile acid absorption. ASBTi’s show effects that are quite similar to those obtained with BAS, which is anticipated when considering that accelerated faecal loss of bile acids is compensated by an increased hepatic synthesis of bile acids from cholesterol. Oppositely, treatment with farnesoid X receptor agonists, resulting in inhibition of bile acid synthesis, appears to be associated with increased LDL cholesterol. In conclusion, the increasing efforts to employ drugs that intervene in bile acid metabolism and signalling pathways for the treatment of metabolic diseases such as NAFLD warrants reinforcing interactions between the bile acid and lipid and lipoprotein research fields. This review may be considered as the first step in this process

Means and methods for modulating lipid metabolism

The invention relates to means and methods for the modulation of lipid metabolism in an individual. Among others, it relates to a novel regulator of levels of plasma lipids and hepatic lipids and the use thereof for therapeutic intervention. Provided is a modulator of the Small leucine-rich protein 1 (human) (SMLR1) gene, a SMLR1 gene product, and/or a transcriptional regulator of SMLR1. Also provided is the use of the SMLR1 gene, a SMLR1 gene product, and/or a transcriptional regulator of SMLR1, as target in a method of modulating lipid metabolism in a subject

Managing of Dyslipidaemia Characterized by Accumulation of Triglyceride-Rich Lipoproteins

PURPOSE OF REVIEW: The accumulation of triglyceride-rich lipoproteins (TRLs) in plasma in patients with familial chylomicronaemia syndrome (FCS) or severe hypertriglyceridemia is associated with an increased risk of potentially life-threatening pancreatitis. Elevated TRL levels have also been suggested to contribute to atherosclerotic cardiovascular disease (ASCVD). This review provides the latest progress that has been made in this field of research. RECENT FINDINGS: Apolipoprotein C-III and angiopoietin-like protein 3 play key roles in the metabolism of TRLs. Targeting their production in the liver or their presence in the circulation effectively reduces triglycerides in patients with FCS or severe hypertriglyceridemia. Attempts to reduce triglyceride synthesis in the small intestine have been halted. Early studies with a fibroblast growth factor 21 agonist have shown to reduce plasma triglycerides and hepatic steatosis and improve glucose homeostasis. SUMMARY: New drugs have recently been shown to effectively reduce plasma triglycerides which render hope for treating the risk of pancreatitis. Studies that have just been initiated will learn whether this unmet clinical will be met. It is too early to evaluate the potential of these drugs to reduce the risk of atherosclerosis through the reduction of triglycerides

Emerging small molecule drugs

Dyslipidaemia is a major risk factor for cardiovascular diseases. Pharmacological lowering of LDL-C levels using statins reduces cardiovascular risk. However, a substantial residual risk persists especially in patients with type 2 diabetes mellitus. Because of the inverse association observed in epidemiological studies of HDL-C with the risk for cardiovascular diseases, novel therapeutic strategies to raise HDL-C levels or improve HDL functionality are developed as complementary therapy for cardiovascular diseases. However, until now most therapies targeting HDL-C levels failed in clinical trials because of side effects or absence of clinical benefits. This chapter will highlight the emerging small molecules currently developed and tested in clinical trials to pharmacologically modulate HDL-C and functionality including new CETP inhibitors (anacetrapib, evacetrapib), novel PPAR agonists (K-877, CER-002, DSP-8658, INT131 and GFT505), LXR agonists (ATI-111, LXR-623, XL-652) and RVX-208

Forward Individualized Medicine from Personal Genomes to Interactomes

When considering the variation in the genome, transcriptome, proteome and metabolome, and their interaction with the environment, every individual can be rightfully considered as a unique biological entity. Individualized medicine promises to take this uniqueness into account to optimize disease treatment and thereby improve health benefits for every patient. The success of individualized medicine relies on a precise understanding of the genotype-phenotype relationship. Although omics technologies advance rapidly, there are several challenges that need to be overcome: Next generation sequencing can efficiently decipher genomic sequences, epigenetic changes, and transcriptomic variation in patients, but it does not automatically indicate how or whether the identified variation will cause pathological changes. This is likely due to the inability to account for (1) the consequences of gene-gene and gene-environment interactions, and (2) (post)transcriptional as well as (post)translational processes that eventually determine the concentration of key metabolites. The technologies to accurately measure changes in these latter layers are still under development, and such measurements in humans are also mainly restricted to blood and circulating cells. Despite these challenges, it is already possible to track dynamic changes in the human interactome in healthy and diseased states by using the integration of multi-omics data. In this review, we evaluate the potential value of current major bioinformatics and systems biology-based approaches, including genome wide association studies, epigenetics, gene regulatory and protein-protein interaction networks, and genome-scale metabolic modeling. Moreover, we address the question whether integrative analysis of personal multi-omics data will help understanding of personal genotype-phenotype relationships

Identification of Discriminating Metabolic Pathways and Metabolites in Human PBMCs Stimulated by Various Pathogenic Agents

Immunity and cellular metabolism are tightly interconnected but it is not clear whether different pathogens elicit specific metabolic responses. To address this issue, we studied differential metabolic regulation in peripheral blood mononuclear cells (PBMCs) of healthy volunteers challenged by Candida albicans, Borrelia burgdorferi, lipopolysaccharide, and Mycobacterium tuberculosis in vitro. By integrating gene expression data of stimulated PBMCs of healthy individuals with the KEGG pathways, we identified both common and pathogen-specific regulated pathways depending on the time of incubation. At 4 h of incubation, pathogenic agents inhibited expression of genes involved in both the glycolysis and oxidative phosphorylation pathways. In contrast, at 24 h of incubation, particularly glycolysis was enhanced while genes involved in oxidative phosphorylation remained unaltered in the PBMCs. In general, differential gene expression was less pronounced at 4 h compared to 24 h of incubation. KEGG pathway analysis allowed differentiation between effects induced by Candida and bacterial stimuli. Application of genome-scale metabolic model further generated a Candida-specific set of 103 reporter metabolites (e.g., desmosterol) that might serve as biomarkers discriminating Candida stimulated PBMCs from bacteria-stimuated PBMCs. Our analysis also identified a set of 49 metabolites that allowed discrimination between the effects of Borrelia burgdorferi, lipopolysaccharide and Mycobacterium tuberculosis. We conclude that analysis of pathogen-induced effects on PBMCs by a combination of KEGG pathways and genome-scale metabolic model provides deep insight in the metabolic changes coupled to host defense

Sharing lessons learnt across European cardiovascular research consortia

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