Caloric restriction and intermittent fasting are known to prolong life-and healthspan in model organisms, while their effects on humans are less well studied. In a randomized controlled trial study (ClinicalTrials.gov identifier: NCT02673515), we show that 4 weeks of strict alternate day fasting (ADF) improved markers of general health in healthy, middle-aged humans while causing a 37% calorie reduction on average. No adverse effects occurred even after >6 months. ADF improved cardiovascular markers, reduced fat mass (particularly the trunk fat), improving the fat-tolean ratio, and increased b-hydroxybutyrate, even on non-fasting days. On fasting days, the pro-aging amino-acid methionine, among others, was periodically depleted, while polyunsaturated fatty acids were elevated. We found reduced levels sICAM-1 (an age-associated inflammatory marker), low-density lipoprotein, and the metabolic regulator triiodothyronine after long-term ADF. These results shed light on the physiological impact of ADF and supports its safety. ADF could eventually become a clinically relevant intervention.

In obese individuals, atherogenic dyslipidemia is a very common and important factor in the increased risk of cardiovascular disease. Adiposity-associated dyslipidemia is characterized by low high-density lipoprotein cholesterol (HDL-C) levels and an increase in triglyceride-rich lipoproteins. Several factors and mechanisms are involved in lowering HDL-C levels in the obese state and HDL quantity and quality is closely related to adiponectin levels and the bioactive lipid sphingosine-1-phosphate. Recent studies have shown that obesity profoundly alters HDL metabolism, resulting in altered HDL subclass distribution, composition, and function. Importantly, weight loss through gastric bypass surgery and Mediterranean diet, especially when enriched with virgin olive oil, is associated with increased HDL-C levels and significantly improved metrics of HDL function. A thorough understanding of the underlying mechanisms is crucial for a better understanding of the impact of obesity on lipoprotein metabolism and for the development of appropriate therapeutic approaches. The objective of this review article was to summarize the newly identified changes in the metabolism, composition, and function of HDL in obesity and to discuss possible pathophysiological consequences.

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In the general population, the ability of high-density lipoproteins (HDLs) to promote cholesterol efflux is a predictor of cardiovascular events, independently of HDL cholesterol levels. Although patients with chronic kidney disease (CKD) have a high burden of cardiovascular morbidity and mortality, neither serum levels of HDL cholesterol, nor cholesterol efflux capacity associate with cardiovascular events. Important for the following discussion on the role of HDL in CKD is the notion that traditional atherosclerotic cardiovascular risk factors only partially account for this increased incidence of cardiovascular disease in CKD. As a potential explanation, across the spectrum of cardiovascular disease, the relative contribution of atherosclerotic cardiovascular disease becomes less important with advanced CKD. Impaired renal function directly affects the metabolism, composition and functionality of HDL particles. HDLs themselves are a heterogeneous population of particles with distinct sizes and protein composition, all of them affecting the functionality of HDL. Therefore, a more specific approach investigating the functional and compositional features of HDL subclasses might be a valuable strategy to decipher the potential link between HDL, cardiovascular disease and CKD. This review summarizes the current understanding of the relationship of HDL composition, metabolism and function to their cardio-protective properties in CKD, with a focus on CKD-induced changes in the HDL proteome and reverse cholesterol transport capacity. We also will highlight the gaps in the current knowledge regarding important aspects of HDL biology.