Current opinion in lipidology最新文献

Purpose of review: To review the evidence and describe the biological plausibility for the benefits of inhibiting cholesteryl ester transfer protein (CETP) on multiple organ systems through modification of lipoprotein metabolism.

Recent findings: Results from observational studies, Mendelian randomization analyses, and randomized clinical trials support the potential of CETP inhibition to reduce atherosclerotic cardiovascular disease (ASCVD) risk through a reduction of apolipoprotein B-containing lipoproteins. In contrast, raising high-density lipoprotein (HDL) particles, as previously hypothesized, did not contribute to ASCVD risk reduction. There is also an expanding body of evidence supporting the benefits of CETP inhibition for safeguarding against other conditions associated with aging, particularly new-onset type 2 diabetes mellitus and dementia, as well as age-related macular degeneration, septicemia, and possibly chronic kidney disease. The latter are likely mediated through improved functionality of the HDL particle, including its role on cholesterol efflux and antioxidative, anti-inflammatory, and antimicrobial activities.

Summary: At present, there is robust clinical evidence to support the benefits of reducing CETP activity for ASCVD risk reduction, and plausibility exists for the promotion of longevity by reducing risks of several other conditions. An ongoing large clinical trial program of the latest potent CETP inhibitor, obicetrapib, is expected to provide further insight into CETP inhibition as a therapeutic target for these various conditions.

Purpose of review: This review examines the impact of glucagon-like peptide 1 receptor agonists (GLP-1RAs) on lipid profiles in individuals with type 2 diabetes mellitus and/or obesity, crucial for optimizing cardiovascular risk management.

Recent findings: GLP-1RAs affect lipid levels by reducing intestinal apolipoprotein B48 production and mesenteric lymph flow, while increasing catabolism of apolipoprotein B100. It remains unknown whether these effects are direct or indirect, but the improvements in lipid levels are strongly correlated to the drug-induced weight loss. Clinical trials demonstrate improvements in lipid profiles, with different effects per agent and dose. We deem it unlikely that improved lipid levels are sufficient to explain the beneficial effects of GLP-1RA on cardiovascular risk, especially given the improvement of many other risk factors (body weight, glycemic control, inflammation) while using these agents. Posthoc mediation analyses of large cardiovascular outcome trials may shed some light on the relative importance of each risk factor.

Summary: GLP-1RAs improve lipid profiles in clinical trials, but their complete cardiovascular benefits likely involve multifactorial mechanisms beyond lipid modulation.

Purpose of review: Inhibitors of sodium-glucose cotransporter-2 (SGLT2) lower renal glucose reabsorption and, thus, are used to treat patients with type 2 diabetes mellitus. Clinical trials coincidentally showed that SGLT2 inhibitors also benefitted patients with heart failure. This review explores the impact of SGLT2 inhibitors on other aspects of cardiovascular disease and skeletal health.

Recent findings: In some, but not all, clinical and preclinical studies, SGLT2 inhibitors are found to reduce serum levels of free fatty acids and triglycerides. Their effects on total and low-density lipoprotein cholesterol and cardiac function also vary. However, SGLT2 inhibitors reduce lipid accumulation in the liver, kidney, and heart, and alter expression of lipid metabolism genes. Effects on free fatty acid uptake in abdominal fat depots depend on the location of adipose tissue. In male, but not female, mice, SGLT2 inhibitors reduce the atherosclerotic lesions and aortic calcium deposition. With respect to skeletal health, recent literature has reported conflicting associations with the risks of fracture and amputation.

Summary: Studies suggest that SGLT2 inhibitors reduce tissue lipid accumulation, and in a sex-dependent manner, atherosclerosis and vascular calcification. However, their effects on lipid levels and bone health are complex and remain to be established.

Purpose of review: To review recent publications linking the intestine to cardiovascular disease.

Recent findings: Aromatic amino acid-derived metabolites produced by gut-bacteria were identified that increased or decreased the risk of cardiovascular events. Dietary phenylalanine was metabolized to phenylacetic acid by gut microbes, and converted into phenylacetylglutamine by the host, which increased thrombosis potential via adrenergic receptors and was associated with increased major adverse cardiovascular events. Another microbiota-associated metabolite of aromatic amino acids, indole-3-propionic acid, protected against heart failure with preserved ejection fraction. The mechanism by which dietary cholesterol is absorbed was found to involve the Nieman-Pick C1-like1 protein working together with a newly discovered protein called Aster. Levels of gut-derived bacterial lipopolysaccharide in serum that are an order of magnitude less than those seen in gram negative sepsis were shown to play a role in enhancing atherosclerosis and thrombosis.

Summary: Promising new therapeutic targets in the intestine for preventing or treating cardiovascular disease have been identified.

Purpose of review: Proton nuclear magnetic resonance (NMR) can rapidly assess lipoprotein concentrations and sizes in biological samples. It may be especially useful for quantifying high-density lipoprotein (HDL), which exhibits diverse particle sizes and concentrations. We provide a critical review of the strengths and limitations of NMR for quantifying HDL subclasses.

Recent findings: Recent studies using NMR have shed light on HDL's role in various disorders, ranging from residual cardiovascular risk to host susceptibility to infection. However, accurately quantifying HDL particle number, size, and concentration (HDL-P) remains a challenge. Discrepancies exist between NMR and other methods such as gel electrophoresis, ion mobility analysis and size-exclusion chromatography in estimating the abundance of HDL species and the ratio of apolipoprotein A-I (APOA1) to HDL particles.

Summary: NMR is a low-cost method for quantifying HDL-P that is readily applicable to clinical and translational studies. However, inconsistencies between the results of NMR quantification of HDL-P and other independent methods hinder the interpretation of NMR results. Because proton NMR apparently fails to accurately quantify the sizes and concentrations of HDL, the relevance of such studies to HDL biology poses challenges. This limits our understanding of pathophysiological implications of HDL-P as determined by NMR, particularly in determining cardiovascular disease (CVD) risk.

Purpose of review: This review examines the evolving role of the fat-inducing transcript 2 (FIT2) protein in lipid droplet (LD) biology and its broader implications in cellular physiology and disease. With recent advancements in understanding FIT2 function across various model systems, this review provides a timely synthesis of its mechanisms and physiological significance.

Recent findings: FIT2, an endoplasmic reticulum (ER)-resident protein, has been established as a critical regulator of LD formation in diverse organisms, from yeast to mammals. It facilitates LD biogenesis by sequestering diacylglycerol (DAG) and potentially influencing ER membrane dynamics. Beyond its role in lipid metabolism, FIT2 intersects with the ER-associated degradation (ERAD), is critical for protein homeostasis, and is linked to the unfolded protein response (UPR). Dysregulation of FIT2 has also been linked to metabolic disorders such as insulin resistance and lipodystrophy, highlighting its clinical relevance.

Summary: Insights into FIT2 function underscore its pivotal role in LD formation and lipid homeostasis. Understanding its involvement in ER proteostasis and very low density lipoprotein biogenesis has broad implications for metabolic diseases and cancer. Therapeutic strategies targeting FIT2 may offer novel approaches to modulate lipid metabolism and mitigate associated pathologies. Further research is needed to elucidate the full spectrum of FIT2's interactions within cellular lipid and protein networks, potentially uncovering new therapeutic avenues for metabolic and ER stress-related disorders.

Purpose of review: There are no current drug therapies to limit abdominal aortic aneurysm (AAA) growth. This review summarizes evidence suggesting that inhibiting proprotein convertase subtilisin/kexin type 9 (PCSK9) may be a drug target to limit AAA growth.

Recent findings: Mendelian randomization studies suggest that raised LDL and non-HDL-cholesterol are causal in AAA formation. PCSK9 was reported to be upregulated in human AAA samples compared to aortic samples from organ donors. PCSK9 gain of function viral vectors promoted aortic expansion in C57BL/6 mice infused with angiotensin II. The effect of altering PCSK9 expression in the aortic perfusion elastase model was reported to be inconsistent. Mutations in the gene encoding PCSK9, which increase serum cholesterol, were associated with increased risk of human AAA. Patients with AAA also have a high risk of cardiovascular death, myocardial infarction and stroke. Recent research suggests that PCSK9 inhibition would substantially reduce the risk of these events.

Summary: Past research suggests that drugs that inhibit PCSK9 have potential as a novel therapy for AAA to both limit aneurysm growth and reduce risk of cardiovascular events. A large multinational randomized controlled trial is needed to test if PCSK9 inhibition limits AAA growth and cardiovascular events.

Purpose of review: There is growing literature that supports the testing of Lp(a). However, few patients are tested, including those with a personal or family history of cardiovascular disease (CVD). One often noted barrier to more widespread testing is uncertainty regarding what to do with an elevated Lp(a) level. Although guidelines vary, there is agreement on the use of Lp(a) as a risk enhancer to guide medical care and shared decision-making. This review will discuss a clinical approach with supporting evidence for management of patients with elevated Lp(a).

Recent findings: At the minimum, elevated Lp(a) increases cardiovascular risk and can be incorporated into existing risk stratification paradigms. The cornerstone of management is aggressive management of traditional cardiovascular risk factors, including LDL-cholesterol (LDL-C). More recent studies have highlighted the potential role for proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i), aspirin in primary prevention, and prolonged dual antiplatelet therapy in secondary prevention.

Summary: Although there is optimism for Lp(a)-targeted therapies in the near future, an elevated Lp(a) level is actionable today, and uncertainty regarding the management of patients with elevated Lp(a) should not be a barrier to more widespread testing.