-
Archives of Toxicology Nov 2023Pharmaceuticals and environmental contaminants contribute to hypercholesterolemia. Several chemicals known to cause hypercholesterolemia, activate pregnane X receptor... (Review)
Review
Pharmaceuticals and environmental contaminants contribute to hypercholesterolemia. Several chemicals known to cause hypercholesterolemia, activate pregnane X receptor (PXR). PXR is a nuclear receptor, classically identified as a sensor of chemical environment and regulator of detoxification processes. Later, PXR activation has been shown to disrupt metabolic functions such as lipid metabolism and recent findings have shown PXR activation to promote hypercholesterolemia through multiple mechanisms. Hypercholesterolemia is a major causative risk factor for atherosclerosis and greatly promotes global health burden. Metabolic disruption by PXR activating chemicals leading to hypercholesterolemia represents a novel toxicity pathway of concern and requires further attention. Therefore, we constructed an adverse outcome pathway (AOP) by collecting the available knowledge considering the molecular mechanisms for PXR-mediated hypercholesterolemia. AOPs are tools of modern toxicology for systematizing mechanistic knowledge to assist health risk assessment of chemicals. AOPs are formalized and structured linear concepts describing a link between molecular initiating event (MIE) and adverse outcome (AO). MIE and AO are connected via key events (KE) through key event relationships (KER). We present a plausible route of how PXR activation (MIE) leads to hypercholesterolemia (AO) through direct regulation of cholesterol synthesis and via activation of sterol regulatory element binding protein 2-pathway.
Topics: Humans; Hypercholesterolemia; Adverse Outcome Pathways; Pregnane X Receptor; Risk Assessment; Lipid Metabolism
PubMed: 37642746
DOI: 10.1007/s00204-023-03575-4 -
Diabetologia Dec 2023Elevated remnant cholesterol is observationally and causally associated with increased risk of atherosclerotic cardiovascular disease (ASCVD) in the general population....
AIMS/HYPOTHESIS
Elevated remnant cholesterol is observationally and causally associated with increased risk of atherosclerotic cardiovascular disease (ASCVD) in the general population. This association is not well studied in individuals with diabetes, who are often included in clinical trials of remnant cholesterol-lowering therapy. We tested the hypothesis that elevated remnant cholesterol is associated with increased risk of ASCVD in individuals with diabetes. We also explored the fraction of excess risk conferred by diabetes which can be explained by elevated remnant cholesterol.
METHODS
We included 4569 white Danish individuals with diabetes (58% statin users) nested within the Copenhagen General Population Study (2003-2015). The ASCVDs peripheral artery disease, myocardial infarction and ischaemic stroke were extracted from national Danish health registries without losses to follow-up. Remnant cholesterol was calculated from a standard lipid profile.
RESULTS
During up to 15 years of follow-up, 236 individuals were diagnosed with peripheral artery disease, 234 with myocardial infarction, 226 with ischaemic stroke and 498 with any ASCVD. Multivariable adjusted HR (95% CI) per doubling of remnant cholesterol was 1.6 (1.1, 2.3; p=0.01) for peripheral artery disease, 1.8 (1.2, 2.5; p=0.002) for myocardial infarction, 1.5 (1.0, 2.1; p=0.04) for ischaemic stroke, and 1.6 (1.2, 2.0; p=0.0003) for any ASCVD. Excess risk conferred by diabetes was 2.5-fold for peripheral artery disease, 1.6-fold for myocardial infarction, 1.4-fold for ischaemic stroke and 1.6-fold for any ASCVD. Excess risk explained by elevated remnant cholesterol and low-grade inflammation was 14% and 8% for peripheral artery disease, 26% and 16% for myocardial infarction, 34% and 34% for ischaemic stroke, and 24% and 18% for any ASCVD, respectively. LDL-cholesterol did not explain excess risk, as it was not higher in individuals with diabetes. We also explored the fraction of excess risk conferred by diabetes which can be explained by elevated remnant cholesterol.
CONCLUSIONS/INTERPRETATION
Elevated remnant cholesterol was associated with increased risk of ASCVD in individuals with diabetes. Remnant cholesterol and low-grade inflammation explained substantial excess risk of ASCVD conferred by diabetes. Whether remnant cholesterol should be used as a treatment target remains to be determined in randomised controlled trials.
Topics: Humans; Cardiovascular Diseases; Prospective Studies; Brain Ischemia; Stroke; Atherosclerosis; Cholesterol; Diabetes Mellitus; Hypercholesterolemia; Inflammation; Myocardial Infarction; Peripheral Arterial Disease; Ischemic Stroke; Risk Factors
PubMed: 37776347
DOI: 10.1007/s00125-023-06016-0 -
Clinical Genetics Jan 2024Lipid disorders play a critical role in the intricate development of atherosclerosis and its clinical consequences, such as coronary heart disease and stroke. These... (Review)
Review
Lipid disorders play a critical role in the intricate development of atherosclerosis and its clinical consequences, such as coronary heart disease and stroke. These disorders are responsible for a significant number of deaths in many adult populations worldwide. Familial hypercholesterolemia (FH) is a genetic disorder that causes extremely high levels of LDL cholesterol. The most common mutations occur in genes responsible for low-density lipoprotein receptor (LDLR), apolipoprotein B (APOB), or proprotein convertase subtilisin/kexin type 9 (PCSK9). While genetic testing is a dependable method for diagnosing the disease, it may not detect primary mutations in 20%-40% of FH cases.
Topics: Adult; Humans; Proprotein Convertase 9; Hyperlipoproteinemia Type II; Cholesterol, LDL; Genetic Background; Receptors, LDL
PubMed: 37849044
DOI: 10.1111/cge.14435 -
Expert Opinion on Therapeutic Patents Apr 2024Proprotein convertase subtilisin/kexin 9 (PCSK9) plays a crucial role in breaking down the hepatic low-density lipoprotein receptor (LDLR), thereby influencing the... (Review)
Review
INTRODUCTION
Proprotein convertase subtilisin/kexin 9 (PCSK9) plays a crucial role in breaking down the hepatic low-density lipoprotein receptor (LDLR), thereby influencing the levels of circulating low-density lipoprotein cholesterol (LDL-C). Consequently, inhibiting PCSK9 through suitable ligands has been established as a validated therapeutic strategy for combating hypercholesterolemia and cardiovascular diseases.
AREA COVERED
Patent literature claiming novel compounds inhibiting PCSK9 disclosed from 2018 to June 2023 available in the espacenet database, which contains more than 150 million patent documents from over 100 patent-granting authorities worldwide.
EXPERT OPINION
The undisputable beneficial influence of PCSK9 as a pharmacological target has prompted numerous private and public institutions to patent chemical frameworks as inhibitors of PCSK9. While several compounds have advanced to clinical trials for treating hypercholesterolemia, they have not completed these trials yet. These compounds must contend in a complex market where new, costly, and advanced drugs, such as monoclonal antibodies and siRNA, are prescribed instead of inexpensive and less potent statins.
Topics: Patents as Topic; Humans; PCSK9 Inhibitors; Hypercholesterolemia; Animals; Proprotein Convertase 9; Cholesterol, LDL; Anticholesteremic Agents; Cardiovascular Diseases; Drug Development; Receptors, LDL
PubMed: 38588538
DOI: 10.1080/13543776.2024.2340569 -
Hormones (Athens, Greece) Dec 2023Hypercholesterolemia due to a high-cholesterol diet is linked to numerous diseases and may lead to male infertility. However, the underlying mechanism remains unknown....
PURPOSE
Hypercholesterolemia due to a high-cholesterol diet is linked to numerous diseases and may lead to male infertility. However, the underlying mechanism remains unknown. The maintenance of male fertility requires intact testicular structures (including seminiferous tubules and mesenchyme) and functioning cells (Leydig cells, Sertoli cells and germ cells, etc.), production of appropriate concentrations of sex hormones, and cooperation among testicular cells. Thus, we considered whether male fertility declined as the structure and function of testicular cells were altered in rats on a high-cholesterol diet.
METHODS
Male Sprague Dawley rats were fed either a standard or a high-cholesterol diet for 16 weeks. Serum sex hormones, lipid components, semen quality, and fertility rate were assayed in the rats. The 3β-hydroxysteroid dehydrogenase (3β-HSD), Wilms tumor 1 (WT-1), and deleted in azoospermia-like (DAZL) were regarded as specific markers of Leydig, Sertoli, and germ cells in rats. In addition, the ultrastructure of the testis and expression levels of particular marker molecules of testicular cells were further investigated.
RESULTS
Compared to rats fed on a regular diet, the serum testosterone levels and sperm progressive motility decreased in rats fed high cholesterol. Moreover, we observed a deformed nucleus, dilated smooth endoplasmic reticulum, and swollen mitochondria of Leydig cells and a schizolytic nucleus of Sertoli cells in rats on a high-cholesterol diet. The 3β-HSD, WT-1, and DAZL protein expression levels were significantly reduced in rats on a high-cholesterol diet.
CONCLUSIONS
Our results showed that a high-cholesterol diet adversely affected testosterone production and sperm progressive motility, possibly due to Leydig, Sertoli, and germ cell abnormalities.
Topics: Humans; Male; Rats; Animals; Hypercholesterolemia; Semen Analysis; Rats, Sprague-Dawley; Semen; Testis; Leydig Cells; Testosterone; Testicular Diseases; Diet; Cholesterol
PubMed: 37596375
DOI: 10.1007/s42000-023-00472-4 -
Deutsche Medizinische Wochenschrift... Aug 2023Pharmacological reduction of LDL-cholesterol (LDL-C) is a major treatment strategy in limiting atherosclerotic cardiovascular (ASCVD) risk. Statins remain the primary...
Pharmacological reduction of LDL-cholesterol (LDL-C) is a major treatment strategy in limiting atherosclerotic cardiovascular (ASCVD) risk. Statins remain the primary therapeutic cornerstone in ASCVD prevention. Furthermore, ezetimibe, bempedoic acid, and PCSK9 inhibition have recently also shown to reduce cardiovascular risk. Unfortunately, a treatment gap remains between guideline-recommended LDL-C goals and what is achieved in real-world practice. An important reason for this is the limited use of novel and effective non-statin lipid-lowering therapies. In order to achieve LDL-C treatment goals and, ultimately, reduction of cardiovascular events, a combination lipid-lowering therapy needs to be considered as the standard of care for patients at very high cardiovascular risk.
Topics: Humans; Hypercholesterolemia; Proprotein Convertase 9; Cholesterol, LDL; Anticholesteremic Agents; Cardiovascular Diseases; Risk Factors; Hyperlipidemias; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Atherosclerosis; Heart Disease Risk Factors; Ezetimibe
PubMed: 37541292
DOI: 10.1055/a-1932-6448 -
Diabetes & Metabolism Journal Sep 2023This study aimed to investigate the prevalence and status of dyslipidemia management among South Korean adults, as performed by the Korean Society of Lipid and...
BACKGRUOUND
This study aimed to investigate the prevalence and status of dyslipidemia management among South Korean adults, as performed by the Korean Society of Lipid and Atherosclerosis under the name Dyslipidemia Fact Sheet 2022.
METHODS
We analyzed the lipid profiles, age-standardized and crude prevalence, management status of hypercholesterolemia and dyslipidemia, and health behaviors among Korean adults aged ≥20 years, using the Korea National Health and Nutrition Examination Survey data between 2007 and 2020.
RESULTS
In South Korea, the crude prevalence of hypercholesterolemia (total cholesterol ≥240 mg/dL or use of a lipid-lowering drug) in 2020 was 24%, and the age-standardized prevalence of hypercholesterolemia more than doubled from 2007 to 2020. The crude treatment rate was 55.2%, and the control rate was 47.7%. The crude prevalence of dyslipidemia-more than one out of three conditions (low-density lipoprotein cholesterol ≥160 or the use of a lipid-lowering drug, triglycerides ≥200, or high-density lipoprotein cholesterol [HDL-C] [men and women] <40 mg/dL)-was 40.2% between 2016 and 2020. However, it increased to 48.2% when the definition of hypo-HDL-cholesterolemia in women changed from <40 to <50 mg/dL.
CONCLUSION
Although the prevalence of hypercholesterolemia and dyslipidemia has steadily increased in South Korea, the treatment rate remains low. Therefore, continuous efforts are needed to manage dyslipidemia through cooperation between the national healthcare system, patients, and healthcare providers.
Topics: Adult; Male; Humans; Female; Hypercholesterolemia; Nutrition Surveys; Risk Factors; Dyslipidemias; Cholesterol, LDL; Republic of Korea
PubMed: 37528532
DOI: 10.4093/dmj.2023.0135 -
Current Opinion in Lipidology Dec 2023Familial hypercholesterolemia is associated with an increased risk of cardiovascular disease. The current international guidelines of the main scientific societies... (Review)
Review
PURPOSE OF REVIEW
Familial hypercholesterolemia is associated with an increased risk of cardiovascular disease. The current international guidelines of the main scientific societies consider that, all people with Familial Hypercholesterolemia have a high or very high cardiovascular risk. However, the occurrence of atherosclerotic cardiovascular disease is very heterogeneous in this population. Stratifying risk within people with familial hypercholesterolemia is essential to identify individuals who require intensive cholesterol-lowering therapies.
RECENT FINDINGS
In the last year, several studies have been published focusing on the contribution of diabetes to Familial Hypercholesterolemia, the role of stroke, as a manifestation of atherosclerotic disease, and the external validation of the SAFEHEART risk equation in the English population diagnosed with Familial Hypercholesterolemia.
SUMMARY
It is necessary the development of a tool that allows us to identify, in a simple, reproducible, and universal way, patients who may have a high risk of suffering a cardiovascular event and who are susceptible to more intensive treatments to reduce cholesterol levels.
Topics: Humans; Cardiovascular Diseases; Risk Factors; Hyperlipoproteinemia Type II; Cholesterol, LDL; Atherosclerosis; Heart Disease Risk Factors
PubMed: 37769168
DOI: 10.1097/MOL.0000000000000903 -
Arteriosclerosis, Thrombosis, and... Oct 2023Severe hypercholesterolemia, defined as LDL (low-density lipoprotein) cholesterol (LDL-C) measurement ≥190 mg/dL, is associated with increased risk for coronary artery...
BACKGROUND
Severe hypercholesterolemia, defined as LDL (low-density lipoprotein) cholesterol (LDL-C) measurement ≥190 mg/dL, is associated with increased risk for coronary artery disease (CAD). Causes of severe hypercholesterolemia include monogenic familial hypercholesterolemia, polygenic hypercholesterolemia, elevated lipoprotein(a) [Lp(a)] hypercholesteremia, polygenic hypercholesterolemia with elevated Lp(a) (two-hit), or nongenetic hypercholesterolemia. The added value of using a genetics approach to stratifying risk of incident CAD among those with severe hypercholesterolemia versus using LDL-C levels alone for risk stratification is not known.
METHODS
To determine whether risk stratification by genetic cause provided better 10-year incident CAD risk stratification than LDL-C level, a retrospective cohort study comparing incident CAD risk among severe hypercholesterolemia subtypes (genetic and nongenetic causes) was performed among 130 091 UK Biobank participants. Analyses were limited to unrelated, White British or Irish participants with available exome sequencing data. Participants with cardiovascular disease at baseline were excluded from analyses of incident CAD.
RESULTS
Of 130 091 individuals, 68 416 (52.6%) were women, and the mean (SD) age was 56.7 (8.0) years. Of the cohort, 9.0% met severe hypercholesterolemia criteria. Participants with LDL-C between 210 and 229 mg/dL and LDL-C ≥230 mg/dL showed modest increases in incident CAD risk relative to those with LDL-C between 190 and 209 mg/dL (210-229 mg/dL: hazard ratio [HR], 1.3 [95% CI, 1.1-1.7]; ≥230 mg/dL: HR, 1.3 [95% CI, 1.0-1.7]). In contrast, when risk was stratified by genetic subtype, monogenic familial hypercholesterolemia, elevated Lp(a), and two-hit hypercholesterolemia subtypes had increased rates of incident CAD relative to the nongenetic hypercholesterolemia subtype (monogenic familial hypercholesterolemia: HR, 2.3 [95% CI, 1.4-4.0]; elevated Lp(a): HR, 1.5 [95% CI, 1.2-2.0]; two-hit: HR, 1.9 [95% CI, 1.4-2.6]), while polygenic hypercholesterolemia did not.
CONCLUSIONS
Genetics-based subtyping for monogenic familial hypercholesterolemia and Lp(a) in those with severe hypercholesterolemia provided better stratification of 10-year incident CAD risk than LDL-C-based stratification.
Topics: Humans; Female; Middle Aged; Male; Coronary Artery Disease; Hypercholesterolemia; Cholesterol, LDL; Retrospective Studies; Hyperlipoproteinemia Type II; Risk Factors
PubMed: 37589137
DOI: 10.1161/ATVBAHA.123.319341 -
Aging Nov 2023Mild cognitive impairment (MCI) is a common symptom observed in people over 60 years old and is found to be aggravated by hypercholesterolemia. Severe neuroinflammation...
Mild cognitive impairment (MCI) is a common symptom observed in people over 60 years old and is found to be aggravated by hypercholesterolemia. Severe neuroinflammation induced by BBB dysfunction and monocyte infiltration might be responsible for neuron damage and cognitive impairment. Atorvastatin is a lipid-lowering drug that is widely applied for the treatment of cardiovascular diseases. However, the potential function of Atorvastatin in hypercholesterolemia-induced MCI remains uncertain. Our research will explore the potential therapeutic function of Atorvastatin in memory deficits induced by chronic hypercholesterolemia. ApoE mice were utilized to mimic the state of chronic hypercholesterolemia and were divided into four groups. Animals in the WT and ApoEgroups were orally administered with normal saline, while WT mice in the Atorvastatin group and ApoE mice in the ApoE+ Atorvastatin group were orally administered with 10 mg/kg/day Atorvastatin. Markedly increased plasma cholesterol levels reduced RI in the long-term memory test and the spatial short-term memory test, declined mobility in the open field test, and downregulated PSD-95 and BDNF were observed in ApoE mice, all of which were signally reversed by Atorvastatin. Moreover, the percentages of brain Ly6C CD45 cells and CD3 CD45 cells, as well as the blood Ly6C CD45 cells, plasma IL-12/IL-23 levels and IL-17 level were found notably increased in ApoE mice, all of which were largely repressed by Atorvastatin. Lastly, the increased BBB permeability, decreased ZO-1 and occludin levels, and reduced KLF2 level were markedly abolished by Atorvastatin. Collectively, Atorvastatin mitigated memory deficits and brain monocyte infiltration in ApoE mice.
Topics: Humans; Mice; Animals; Atorvastatin; Hypercholesterolemia; Monocytes; Heptanoic Acids; Pyrroles; Hyperlipidemias; Apolipoproteins E; Brain
PubMed: 38048213
DOI: 10.18632/aging.205217