A Modern Approach to Dyslipidemia Berberich, Amanda J; Hegele, Robert A
Endocrine reviews,
08/2022, Letnik:
43, Številka:
4
Journal Article
Recenzirano
Odprti dostop
Abstract
Lipid disorders involving derangements in serum cholesterol, triglycerides, or both are commonly encountered in clinical practice and often have implications for cardiovascular risk and ...overall health. Recent advances in knowledge, recommendations, and treatment options have necessitated an updated approach to these disorders. Older classification schemes have outlived their usefulness, yielding to an approach based on the primary lipid disturbance identified on a routine lipid panel as a practical starting point. Although monogenic dyslipidemias exist and are important to identify, most individuals with lipid disorders have polygenic predisposition, often in the context of secondary factors such as obesity and type 2 diabetes. With regard to cardiovascular disease, elevated low-density lipoprotein cholesterol is essentially causal, and clinical practice guidelines worldwide have recommended treatment thresholds and targets for this variable. Furthermore, recent studies have established elevated triglycerides as a cardiovascular risk factor, whereas depressed high-density lipoprotein cholesterol now appears less contributory than was previously believed. An updated approach to diagnosis and risk assessment may include measurement of secondary lipid variables such as apolipoprotein B and lipoprotein(a), together with selective use of genetic testing to diagnose rare monogenic dyslipidemias such as familial hypercholesterolemia or familial chylomicronemia syndrome. The ongoing development of new agents—especially antisense RNA and monoclonal antibodies—targeting dyslipidemias will provide additional management options, which in turn motivates discussion on how best to incorporate them into current treatment algorithms.
Dyslipidaemia is characterized by increased blood levels of total or LDL cholesterol and triglycerides, or decreased HDL cholesterol levels, and is a risk factor for cardiovascular disease. ...Dyslipidaemia has a high worldwide prevalence, and many patients are turning to alternatives to pharmacotherapy to manage their lipid levels. Lifestyle modification should be emphasized in all patients to reduce cardiovascular risk and can be initiated before pharmacotherapy in primary prevention of cardiovascular disease. Many functional foods and natural health products have been investigated for potential lipid-lowering properties. Those with good evidence for a biochemical effect on plasma lipid levels include soy protein, green tea, plant sterols, probiotic yogurt, marine-derived omega-3 fatty acids and red yeast rice. Other products such as seaweed, berberine, hawthorn and garlic might confer some limited benefit in certain patient groups. Although none of these products can reduce lipid levels to the same extent as statins, most are safe to use in addition to other lifestyle modifications and pharmacotherapy. Natural health products marketed at individuals with dyslipidaemia, such as policosanol, guggulsterone and resveratrol, have minimal definitive evidence of a biochemical benefit. Additional research is required in this field, which should include large, high-quality randomized controlled trials with long follow-up periods to investigate associations with cardiovascular end points.
Susceptibility to the growing global public health problem of cardiovascular disease is associated with levels of plasma lipids and lipoproteins. Several experimental strategies have helped us to ...clarify the genetic architecture of these complex traits, including classical studies of monogenic dyslipidaemias, resequencing, phenomic analysis and, more recently, genome-wide association studies and analysis of metabolic networks. The genetic basis of plasma lipoprotein levels can now be modelled as a mosaic of contributions from multiple DNA sequence variants, both rare and common, with varying effect sizes. In addition to filling gaps in our understanding of plasma lipoprotein metabolism, the recent genetic advances will improve our ability to classify, diagnose and treat dyslipidaemias.
Graphical Abstract
Graphical Abstract
Metabolic choke points are shown at which apolipoprotein (apo) C-III—depicted in two-dimensional semi-circular form—probably affects triglyceride (TG)-rich ...lipoprotein metabolism. Circled plus (+) and minus (−) signs indicate metabolic steps that apo C-III either promotes or inhibits, respectively. Starting at the upper left (A), dietary fat from the intestine is packaged into chylomicrons (B), which include apo C-III on their surface; apo C-III may promote chylomicron secretion. On the right, TG of endogenous (i.e. hepatic) origin is packaged into very-low-density lipoprotein (VLDL), whose secretion is almost certainly promoted by apo C-III (E). In the plasma space, apo C-III inhibits: (i) lipoprotein lipase (LPL)—indicated in monomeric cartoon form—by impairing the hydrolysis of chylomicrons (C) into chylomicron remnants (D) and of VLDL (F) into intermediate-density lipoprotein (IDL) (G), which is ultimately remodelled into LDL; and (ii) hepatic uptake of TG-rich remnants (D). Interfering with apo C-III production reverses these effects, i.e. reduces secretion of TG-rich lipoproteins (E), increases hydrolysis of TG-rich lipoproteins by LPL (C and F) and permits hepatic removal of TG-rich remnants (D).
Genetics of Hypertriglyceridemia Dron, Jacqueline S.; Hegele, Robert A.
Frontiers in endocrinology,
07/2020, Letnik:
11
Journal Article
Recenzirano
Odprti dostop
Hypertriglyceridemia, a commonly encountered phenotype in cardiovascular and metabolic clinics, is surprisingly complex. A range of genetic variants, from single-nucleotide variants to large-scale ...copy number variants, can lead to either the severe or mild-to-moderate forms of the disease. At the genetic level, severely elevated triglyceride levels resulting from familial chylomicronemia syndrome (FCS) are caused by homozygous or biallelic loss-of-function variants in
LPL, APOC2, APOA5, LMF1
, and
GPIHBP1
genes. In contrast, susceptibility to multifactorial chylomicronemia (MCM), which has an estimated prevalence of ~1 in 600 and is at least 50–100-times more common than FCS, results from two different types of genetic variants: (1) rare heterozygous variants (minor allele frequency <1%) with variable penetrance in the five causal genes for FCS; and (2) common variants (minor allele frequency >5%) whose individually small phenotypic effects are quantified using a polygenic score. There is indirect evidence of similar complex genetic predisposition in other clinical phenotypes that have a component of hypertriglyceridemia, such as combined hyperlipidemia and dysbetalipoproteinemia. Future considerations include: (1) evaluation of whether the specific type of genetic predisposition to hypertriglyceridemia affects medical decisions or long-term outcomes; and (2) searching for other genetic contributors, including the role of genome-wide polygenic scores, novel genes, non-linear gene-gene or gene-environment interactions, and non-genomic mechanisms including epigenetics and mitochondrial DNA.
PDF
