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Finasteride delays atherosclerosis progression in mice and is associated with a reduction in plasma cholesterol in men

ABSTRACT: Finasteride is commonly prescribed to treat benign prostate hyperplasia and male-pattern baldness in cis men and, more recently, trans individuals. However, the effect of finasteride on cardiovascular disease remains elusive. We evaluated the role of finasteride on atherosclerosis using low-density lipoprotein (LDL) receptor-deficient (Ldlr-/-) mice. Next, we examined the relevance to humans by analysing the data deposited between 2009 and 2016 in the National Health and Nutrition Examination Survey (NHANES). We show that finasteride reduces total plasma cholesterol and delays the development of atherosclerosis in Ldlr-/- mice. Finasteride reduced monocytosis, monocyte recruitment to the lesion, macrophage lesion content, and necrotic core area, the latter of which is an indicator of plaque vulnerability in humans. RNA sequencing analysis revealed a downregulation of inflammatory pathways and an upregulation of bile acid metabolism, oxidative phosphorylation, and cholesterol pathways in the liver of mice taking finasteride. Men reporting the use of finasteride showed lower plasma levels of cholesterol and LDL-cholesterol than those not taking the drug. Our data unveil finasteride as a potential treatment to delay cardiovascular disease in people by improving the plasma lipid profile.

ORGANISM(S): Mus musculus

PROVIDER: GSE255708 | GEO | 2024/03/06

REPOSITORIES: GEO

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β-carotene conversion to vitamin A delays atherosclerosis progression by decreasing hepatic lipid secretion in mice

Project description:Atherosclerosis is characterized by the pathological accumulation of cholesterol-laden macrophages in the arterial wall. Atherosclerosis is also the main underlying cause of cardiovascular diseases (CVDs), and its development is largely driven by elevated plasma cholesterol. Strong epidemiological data find an inverse association between plasma β-carotene with atherosclerosis, and we recently showed that β-carotene oxygenase 1 (BCO1) activity, responsible for β-carotene cleavage to vitamin A, is associated with reduced plasma cholesterol in humans and mice. In this study, we explore whether intact β-carotene or vitamin A affect atherosclerosis progression in the atheroprone low-density lipoprotein receptor (LDLR) - deficient mice. In comparison to control-fed Ldlr-/- mice, β-carotene-supplemented mice showed reduced atherosclerotic lesion size at the level of the aortic root and plasma cholesterol levels (P = 0.0003). These changes were absent in Ldlr-/-/Bco1-/- mice, despite accumulating β-carotene in plasma and atherosclerotic lesions. We discarded the implication of myeloid BCO1 in the development of atherosclerosis by performing bone marrow transplant experiments. Lipid production assays found that retinoic acid, the active form of vitamin A, reduced the secretion of newly synthetized triglyceride and cholesteryl ester in cell culture and mice. Overall, our findings provide insights into the role of BCO1 activity and vitamin A in atherosclerosis progression through the regulation of hepatic lipid metabolism.

2020-11-12 | GSE157972 | GEO

Liver gene expression profiles of Tribbles-homolog1 (Trib1)/Ldl-receptor (Ldlr) double-knockout mice against Ldlr-knockout mice

Project description:Genetic variants at the TRIB1 (Tribbles-homolog 1) gene locus are strongly associated with plasma lipid traits and the risk of coronary artery disease in humans. In this study, we analyzed the consequences of Trib1-deficiency (Trib1-/-) on hepatic gene expression in mice on the atherosclerosis-susceptible LDL-receptor deficient (Ldlr-/-) background. Therefore, Trib1-/- mice were crossed onto the Ldlr-/- background to generate double knockout mice (Trib1-/-Ldlr-/-) and fed a semisynthetic, modified AIN76 diet (0.02% cholesterol, 4.3% fat). At 20 weeks of age, Trib1-/-Ldlr-/- mice and Trib1+/+Ldlr-/- control mice were sacrificed and liver tissue was snap frozen in liquid nitrogen and stored at -80°C until further processing. Total RNA was isolated from liver tissue (n=8 mice per genotype) and subjected to microarray gene expression analysis.

2023-03-15 | E-MTAB-12669 | biostudies-arrayexpress

siRNAs induced long-term liver ApoB mRNA knockdown significantly lowers serum cholesterol in a mouse model with human-like serum lipids

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2010-11-22 | E-GEOD-23088 | biostudies-arrayexpress

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2022-09-22 | GSE205008 | GEO

Impaired adult hippocampal neurogenesis in a mouse model of familial hypercholesterolemia: a role for the LDL receptor and cholesterol metabolism in adult neural precursor cells (LDLR Knockdown)

Project description:In familial hypercholesterolemia (FH), mutations in the low-density lipoprotein (LDL) receptor (LDLr) gene result in increased plasma LDL cholesterol. Clinical and preclinical studies revealed an association between FH and hippocampus-related memory and mood impairment. We here asked whether hippocampal pathology in FH might be a consequence of compromised adult hippocampal neurogenesis. We evaluated hippocampus-dependent behaviour and neurogenesis in adult C57BL/6JRj and LDLr-/- mice. Behavioural tests revealed that adult LDLr-/- mice showed reduced performance in a dentate gyrus (DG)-dependent metric change task. This phenotype was accompanied by a reduction in cell proliferation and adult neurogenesis in the DG of LDLr-/- mice, suggesting a potential direct impact of LDLr mutation on NPC. We thus investigated the effects of elevated cholesterol and the function of LDLr in neural precursor cells (NPC) isolated from adult C57BL/6JRj mice in vitro. Exposure of NPC to LDL as well as LDLr gene knockdown reduced proliferation and disrupted transcriptional activity of genes involved in endogenous cholesterol synthesis and metabolism. The LDL treatment also induced an increase in intracellular lipid storage. Functional analysis of differentially expressed genes revealed parallel modulation of distinct regulatory networks upon LDL treatment and LDLr knockdown. Together, these results suggest that high LDL levels and a loss of LDLr function, which are characteristic to individuals with FH, might contribute to a disease-related impairment in adult hippocampal neurogenesis and, consequently, cognitive functions.

2019-09-04 | GSE136797 | GEO

Impaired adult hippocampal neurogenesis in a mouse model of familial hypercholesterolemia: a role for the LDL receptor and cholesterol metabolism in adult neural precursor cells (LDL treatment)

2019-09-04 | GSE136792 | GEO

Atlas of miRNome variations in different dyslipidemic conditions: a study in C57Bl/6, Ldlr-KO, and Pcsk9-KO mice.

Project description:In this study, mice with different genotypes and fed diets with different lipid content were enrolled, aiming to set up an atlas of miRNA expression levels in different organs with a relevant role in lipid/lipoprotein metabolism. Specifically, three genotypes were investigated: C57Bl/6 mice as controls, together with mice knock-out (KO) for LDLr (low-density lipoprotein receptor) and for PCSK9 (proprotein convertase subtilisin/kexin type 9). LDLr and PCSK9 are both involved in LDL turnover, the former mediating LDL clearance [PMID: 19299327], the latter causing the degradation of the LDLr protein [PMID: 17080197]. As a result, LDLrKO mice, because of their impaired LDL catabolism, are hypercholesterolemic and prone to atherosclerosis development, particularly when fed high-fat, cholesterol-containing diets [PMID: 8349823; PMID: 8182121]. On the contrary, PCSK9KO mice, characterized by an accelerated LDL catabolism, are hypocholesterolemic and atherosclerosis resistant [PMID: 15805190]. miRNA expression was investigated in liver, intestine, aorta, white adipose tissue and brain of mice on both standard and Western diet.

2023-09-06 | GSE227578 | GEO

Transcription profiling of blood cells from hypertriglyceridemic men treated with docosahexaenoic acid shows suppression of LDLR and OLR1 gene expression.

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2010-02-21 | E-GEOD-20114 | biostudies-arrayexpress

Therapeutic effects of Rosuvastatin in hypercholesterolemic prediabetic mice in the absence of low density lipoprotein receptor

Project description:Statins are efficient in preventing cardiovascular disease progression, but their effects in the absence of low density lipoprotein receptor (LDLR) and on the risk of diabetes are not yet well characterized. The aim was to clarify systemic and pleiotropic effects of Rosuvastatin on cardiovascular and diabetic phenotypes in hypercholesterolemic prediabetic mice. The IGF-II/LDLR-/-ApoB100/100 animals were tested for Rosuvastatin effects on plasma glucose, insulin, lipids, atherosclerosis and liver steatosis. To achieve a more comprehensive view, genes differentially expressed in response to Rosuvastatin were identified by RNA sequencing in liver tissue. Rosuvastatin significantly reduced plasma cholesterol in hypercholesterolemic LDLR – deficient mice, but had no effects on atherosclerosis development at aortic sinus level and in coronary arteries. Rosuvastatin also significantly reduced liver steatosis without any pronounced effects on glucose or insulin levels. RNA sequencing revealed that Rosuvastatin – responsive hepatic genes are involved in cholesterol metabolism and in anti-inflammatory response. In addition, significant changes were detected in the expression of Perilipin 4 and 5 which are involved in lipid droplet formation in the liver. For the first time it was shown that Tribbles proteins are affected by Rosuvastatin treatment in the hypercholesterolemic mice. In conclusion, Rosuvastatin treatment had several positive effects in hypercholesterolemic mice showing early signs of diabetes, and many of these outcomes are unrelated to direct effects on cholesterol and lipoprotein metabolism. These results increase our understanding about the systemic and pleiotropic effects of Rosuvastatin in the absence of LDLR expression.

2018-11-23 | GSE111125 | GEO

siRNAs induced long-term liver ApoB mRNA knockdown significantly lowers serum cholesterol in a mouse model with human-like serum lipids

2010-11-22 | GSE23088 | GEO

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