Triglyceride-rich lipoproteins and their remnants: metabolic insights, role in atherosclerotic cardiovascular disease, and emerging therapeutic strategies—a consensus statement from the European Atherosclerosis Society

European Heart Journal, Год журнала: 2021, Номер 42(47), С. 4791 - 4806

Опубликована: Июль 30, 2021

Recent advances in human genetics, together with a large body of epidemiologic, preclinical, and clinical trial results, provide strong support for causal association between triglycerides (TG), TG-rich lipoproteins (TRL), TRL remnants, increased risk myocardial infarction, ischaemic stroke, aortic valve stenosis. These data also indicate that their remnants may contribute significantly to residual cardiovascular patients on optimized low-density lipoprotein (LDL)-lowering therapy. This statement critically appraises current understanding the structure, function, metabolism TRL, pathophysiological role atherosclerotic disease (ASCVD). Key points are (i) working definition normo- hypertriglyceridaemic states relation ASCVD, (ii) conceptual framework generation due dysregulation production, lipolysis, remodelling, as well clearance remnant from circulation, (iii) pleiotropic proatherogenic actions at arterial wall, (iv) challenges defining, quantitating, assessing atherogenic properties particles, (v) exploration relative atherogenicity compared LDL. Assessment these issues provides foundation evaluating approaches effectively reduce levels by targeting either or hepatic clearance, combination mechanisms. consensus updates an integrated manner, thereby providing platform new therapeutic paradigms aim reducing ASCVD.

Язык: Английский

---

Metabolic-associated fatty liver disease and lipoprotein metabolism

Molecular Metabolism, Год журнала: 2021, Номер 50, С. 101238 - 101238

Опубликована: Апрель 20, 2021

Non-alcoholic fatty liver disease, or as recently proposed 'metabolic-associated disease' (MAFLD), is characterized by pathological accumulation of triglycerides and other lipids in hepatocytes. This common disease can progress from simple steatosis to steatohepatitis, eventually end-stage diseases. MAFLD closely related disturbances systemic energy metabolism, including insulin resistance atherogenic dyslipidemia. The the central organ lipid metabolism secreting very low density lipoproteins (VLDL) and, on hand, internalizing acids lipoproteins. review article discusses recent research addressing hepatic synthesis, VLDL production, lipoprotein internalization well exchange between adipose tissue context MAFLD. Liver triggered excessive triglyceride synthesis utilizing derived white (WAT), de novo lipogenesis (DNL) endocytosed remnants triglyceride-rich In consequence high content, secretion enhanced, which primary cause complex dyslipidemia typical for subjects with Interventions reducing secretory capacity attenuate while they exacerbate MAFLD, indicating that balance storage versus hepatocytes a critical parameter determining outcome. Proof concept studies have shown promoting combustion tissues reduces load thus ameliorates Moreover, hepatocellular DNL WAT-derived be targeted treat However, more needed understand how individual transporters, enzymes, their isoforms affect vivo, whether these two aspects selectively treated. Processing cholesterol-enriched appears less important steatosis. It may, however, modulate inflammation consequently progression.

Язык: Английский

---

Impact of gastrointestinal tract variability on oral drug absorption and pharmacokinetics: An UNGAP review

European Journal of Pharmaceutical Sciences, Год журнала: 2021, Номер 162, С. 105812 - 105812

Опубликована: Март 20, 2021

The absorption of oral drugs is frequently plagued by significant variability with potentially serious therapeutic consequences. source can be traced back to interindividual in physiology, differences special populations (age- and disease-dependent), drug formulation properties, or food-drug interactions. Clinical evidence for the impact some these factors on pharmacokinetic mounting: e.g. gastric pH emptying time, small intestinal fluid pediatrics elderly, surgical changes gastrointestinal anatomy. However, link colonic (transit composition, microbiome), sex (male vs. female) gut-related diseases (chronic constipation, anorexia cachexia) has not been firmly established yet. At same a way decrease provided pharmaceutical industry: clinical suggests that approaches employed during development exposure. This review outlines main drivers exposure potential overcome them, while highlighting existing knowledge gaps guiding future studies this area.

Язык: Английский

---

Pharmacological Targeting of the Atherogenic Dyslipidemia Complex: The Next Frontier in CVD Prevention Beyond Lowering LDL Cholesterol

Diabetes, Год журнала: 2016, Номер 65(7), С. 1767 - 1778

Опубликована: Июнь 13, 2016

Notwithstanding the effectiveness of lowering LDL cholesterol, residual CVD risk remains in high-risk populations, including patients with diabetes, likely contributed to by non-LDL lipid abnormalities. In this Perspectives Diabetes article, we emphasize that changing demographics and lifestyles over past few decades have resulted an epidemic “atherogenic dyslipidemia complex,” main features which include hypertriglyceridemia, low HDL cholesterol levels, qualitative changes particles, accumulation remnant lipoproteins, postprandial hyperlipidemia. We briefly review underlying pathophysiology form dyslipidemia, particular its association insulin resistance, obesity, type 2 marked atherogenicity condition. explain failure existing classes therapeutic agents such as fibrates, niacin, cholesteryl ester transfer protein inhibitors are known modify components atherogenic complex. Finally, discuss targeted repurposing therapies promising new strategies postulate targeting central abnormality complex, elevation triglyceride-rich lipoprotein represents a frontier prevention is prove most effective strategy correcting aspects thereby preventing events.

Язык: Английский

---

Intestinal lymphatic vasculature: structure, mechanisms and functions

Nature Reviews Gastroenterology & Hepatology, Год журнала: 2017, Номер 14(9), С. 510 - 526

Опубликована: Июнь 28, 2017

Язык: Английский

---

The Role of Gut Microbiota on Cholesterol Metabolism in Atherosclerosis

International Journal of Molecular Sciences, Год журнала: 2021, Номер 22(15), С. 8074 - 8074

Опубликована: Июль 28, 2021

Hypercholesterolemia plays a causal role in the development of atherosclerosis and is one main risk factors for cardiovascular disease (CVD), leading cause death worldwide especially developed countries. Current data show that microbiota extends beyond digestion by being implicated several metabolic inflammatory processes linked to diseases including CVD. Studies have reported associations between bacterial metabolites hypercholesterolemia. However, such remain poorly investigated characterized. In this review, mechanisms microbial derived as primary secondary bile acids (BAs), trimethylamine N-oxide (TMAO), short-chain fatty (SCFAs) will be explored context cholesterol metabolism. These play critical roles maintaining health if dysregulated can potentially contribute They modulated via nutritional pharmacological interventions statins, prebiotics, probiotics. behind these interactions also unclear, mechanistic insights into their impact provided. Therefore, objectives paper are present current knowledge on potential whereby regulate homeostasis discuss feasibility modulating intestinal microbes novel therapeutic

Язык: Английский

---

Mitochondria-rough-ER contacts in the liver regulate systemic lipid homeostasis

Cell Reports, Год журнала: 2021, Номер 34(11), С. 108873 - 108873

Опубликована: Март 1, 2021

Contacts between organelles create microdomains that play major roles in regulating key intracellular activities and signaling pathways, but whether they also regulate systemic functions remains unknown. Here, we report the ultrastructural organization dynamics of inter-organellar contact established by sheets curved rough endoplasmic reticulum closely wrapped around mitochondria (wrappER). To elucidate vivo function this contact, mouse liver fractions enriched wrappER-associated are analyzed transcriptomics, proteomics, lipidomics. The biochemical signature wrappER points to a role biogenesis very-low-density lipoproteins (VLDL). Altering wrappER-mitochondria contacts curtails VLDL secretion increases hepatic fatty acids, lipid droplets, neutral content. Conversely, acute liver-specific ablation Mttp, most upstream regulator biogenesis, recapitulates dyslipidemia phenotype promotes remodeling contact. discovery participate biology suggests an involvement inter-organelle homeostasis.

Язык: Английский

---

Association between dietary patterns and cardiovascular diseases: A review

Current Problems in Cardiology, Год журнала: 2024, Номер 49(3), С. 102412 - 102412

Опубликована: Янв. 24, 2024

Язык: Английский

---

The Complex Interactions Between Obesity, Metabolism and the Brain

Frontiers in Neuroscience, Год журнала: 2019, Номер 13

Опубликована: Май 24, 2019

Obesity is increasing at unprecedented levels globally, and the overall impact of obesity on various organ systems body only beginning to be fully appreciated. Because myriad direct indirect effects causing dysfunction multiple tissues organs, it likely that there will heterogeneity in presentation any given population, its analysis far from linear. The focus this review provide a comprehensive view metabolic disturbances present obesity, their different body, discuss interaction these context aging brain disease.

Язык: Английский

---

Roles of the gut in the metabolic syndrome: an overview

Journal of Internal Medicine, Год журнала: 2016, Номер 281(4), С. 319 - 336

Опубликована: Дек. 19, 2016

Abstract The metabolic syndrome is a cluster of risk factors (central obesity, hyperglycaemia, dyslipidaemia and arterial hypertension), indicating an increased diabetes, cardiovascular disease premature mortality. gastrointestinal tract seldom discussed as organ system principal importance for diseases. present overview connects various research lines into integrative physiological context in which the included. Strong evidence involvement gut derives from powerful effects weight‐reducing (bariatric) surgery. In fact, surgery now recommended standard treatment option type 2 diabetes obesity. Several gut‐related mechanisms that potentially contribute to will be presented. Obesity can caused by hampered release satiety‐signalling hormones, reduced meal‐associated energy expenditure microbiota‐assisted harvest nondigestible food ingredients. Adiposity per se well‐established factor hyperglycaemia. addition, leaky mucosa trigger systemic inflammation mediating peripheral insulin resistance together with blunted incretin response aggravates hyperglycaemic state. intestinal microbiota strongly associated obesity related states, although involved remain unclear. Enterorenal signalling has been suggested pathophysiology hypertension postprandial triglyceride‐rich chylomicrons; cholesterol metabolism probably contributes atherosclerosis. It likely future, treated according novel pharmacological principles interfering functionality.

Язык: Английский

---