Inhibition of squalene synthase upregulates PCSK9 expression in rat liver

Bedi, Mohini; Niesen, Melissa I.; Lopez, Dayami

doi:10.1016/j.abb.2007.11.011

Cited by 17 publications

(11 citation statements)

References 18 publications

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“…One might consider that these cells lack a component or machinery necessary for the coordination of the expression of these proteins, but other research groups have not found a reciprocal regulation of PCSK9 and LDLr. For example, inhibition of squalene synthase upregulates PCSK9 and LDLr expression in rat liver (4) and there was no reverse relation of PCSK9 and LDLr in rat liver cell line (17). PCSK9 was identified as one of the genes that are regulated by SREBPs (24,38).…”

Section: Discussionmentioning

confidence: 98%

Regulation of the proprotein convertase subtilisin/kexin type 9 in intestinal epithelial cells

Leblond

Seidah²,

Précourt³

et al. 2009

American Journal of Physiology-Gastrointestinal and Liver Physi

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Proprotein convertase subtilisin/kexin type 9 (PCSK9) posttranslationally promotes the degradation of the low-density lipoprotein receptor (LDLr) in hepatocytes and increases plasma LDL cholesterol. It is not clear, however, whether PCSK9 plays a role in the small intestine. Here, we characterized the patterns of variations of PCSK9 and LDLr in fully differentiated Caco-2/15 cells as a function of various potential effectors. Cholesterol (100 microM) solubilized in albumin or micelles significantly downregulated PCSK9 gene (30%, P<0.05) and protein expression (50%, P<0.05), surprisingly in concert with a decrease in LDLr protein levels (45%, P<0.05). Cells treated with 25-hydroxycholesterol (50 microM) also displayed significant reduction in PCSK9 gene (37%, P<0.01) and protein (75% P<0.001) expression, whereas LDLr showed a decrease at the gene (30%, P<0.05) and protein (57%, P<0.01) levels, respectively. The amounts of PCSK9 mRNA and protein in Caco-2/15 cells were associated to the regulation of 3-hydroxy-3-methylglutaryl-CoA reductase and sterol regulatory element binding protein-2 (SREBP-2) that can transcriptionally activate PCSK9 via sterol-regulatory elements located in its proximal promoter region. On the other hand, depletion of cholesterol content by hydroxypropyl-beta-cyclodextrin upregulated PCSK9 transcripts (20%, P<0.05) and protein mass (540%, P<0.001), in parallel with SREBP-2 protein levels. The addition of bile acids (BA) taurocholate and deoxycholate to the apical culture medium lowered PCSK9 gene expression (25%, P<0.01) and raised PCSK9 protein expression (30%, P<0.01), respectively, probably via the modulation of farnesoid X receptor. Furthermore, unconjugated and conjugated BA exhibited different effects on PCSK9 and LDLr. Altogether, these data indicate that intestinal PCSK9 is highly modulated by sterols and emphasize the distinct effects of BA species.

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Section: Discussionmentioning

confidence: 98%

Regulation of the proprotein convertase subtilisin/kexin type 9 in intestinal epithelial cells

Leblond

Seidah²,

Précourt³

et al. 2009

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…Modification of serum lipoprotein content, as well as serum withdrawal, induced PCSK9 gene and protein expression in our experiments. PCSK9 was shown to be increased by peroxisome proliferator-activated receptor gamma (PPARγ) ligands [56], bisphosphonate administration [57], statin use or by LXR-agonists [58,59]. On the other hand, farnesoid X Receptor (FXR) agonists, 24(S), 25-epoxycholesterol and the lanosterol synthase inhibitor OSCi decreased PCSK9 expression in human hepatocytes and vascular smooth muscle cells, respectively [58,59].…”

Section: Discussionmentioning

confidence: 99%

ABCC6- a new player in cellular cholesterol and lipoprotein metabolism?

et al. 2014

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BackgroundDysregulations in cholesterol and lipid metabolism have been linked to human diseases like hypercholesterolemia, atherosclerosis or the metabolic syndrome. Many ABC transporters are involved in trafficking of metabolites derived from these pathways. Pseudoxanthoma elasticum (PXE), an autosomal-recessive disease caused by ABCC6 mutations, is characterized by atherogenesis and soft tissue calcification.MethodsIn this study we investigated the regulation of cholesterol biosynthesis in human dermal fibroblasts from PXE patients and healthy controls.ResultsGene expression analysis of 84 targets indicated dysregulations in cholesterol metabolism in PXE fibroblasts. Transcript levels of ABCC6 were strongly increased in lipoprotein-deficient serum (LPDS) and under serum starvation in healthy controls. For the first time, increased HMG CoA reductase activities were found in PXE fibroblasts. We further observed strongly elevated transcript and protein levels for the proprotein convertase subtilisin/kexin type 9 (PCSK9), as well as a significant reduction in APOE mRNA expression in PXE.ConclusionIncreased cholesterol biosynthesis, elevated PCSK9 levels and reduced APOE mRNA expression newly found in PXE fibroblasts could enforce atherogenesis and cardiovascular risk in PXE patients. Moreover, the increase in ABCC6 expression accompanied by the induction of cholesterol biosynthesis supposes a functional role for ABCC6 in human lipoprotein and cholesterol homeostasis.

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“…L-SSKO mice ( 16 ), as reported for HMGCR ( 17,18 ) and PCSK9 ( 19 ) in hepatic cells or livers of rats treated with SS inhibitors. Attenuation of LXR-␣ signaling may also account for the changes in the expression of several genes: SREBP-1c, Cyp7A1, ABCA1, ABCG5, ABCG8 ( 20 ), SR-BI ( 21 ), and apoB ( 22 ).…”

Section: Discussionmentioning

confidence: 99%

Plasma cholesterol-lowering and transient liver dysfunction in mice lacking squalene synthase in the liver

Nagashima

Yagyu

Tozawa

et al. 2015

Journal of Lipid Research

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Mammals have developed sophisticated and complex systems to maintain cellular content of cholesterol, an essential component of cellular membranes and a precursor of bile acids and steroid hormones ( 1 ). In addition to dietary intake, cholesterol is supplied by de novo synthesis from acetate. Squalene synthase (SS; farnesyl-diphosphate farnesyltransferase, EC2.5.1.21) catalyzes the reductive head-to-head condensation of two molecules of farnesyl diphosphate (FPP) to form squalene, the fi rst committed intermediate in the cholesterol biosynthetic pathway ( 2, 3 ). SS contains ‫ف‬ 416 amino acids and is anchored to endoplasmic reticulum by a short C-terminal membrane-spanning domain, with its large N-terminal catalytic domain facing the cytosol, where water-soluble FPP and NADPH are present. Hepatic SS is highly regulated at the transcriptional level, not only by cellular cholesterol content ( 4 ) but also by proinfl ammatory cytokines: TNF-␣ and interleukin 1 ␤ ( 5 ). This enzyme has been an attractive target for cholesterol-lowering therapy because the inhibition of this step theoretically may not perturb the nonsterol pathway, which is a potential problem in the use of statins, inhibitors of HMG-CoA reductase Abstract Squalene synthase (SS) catalyzes the biosynthesis of squalene, the fi rst specifi c intermediate in the cholesterol biosynthetic pathway. To test the feasibility of lowering plasma cholesterol by inhibiting hepatic SS, we generated mice in which SS is specifi cally knocked out in the liver (L-SSKO) using Cre-loxP technology. Hepatic SS activity of L-SSKO mice was reduced by >90%. In addition, cholesterol biosynthesis in the liver slices was almost eliminated. Although the hepatic squalene contents were markedly reduced in L-SSKO mice, the hepatic contents of cholesterol and its precursors distal to squalene were indistinguishable from those of control mice, indicating the presence of suffi cient centripetal fl ow of cholesterol and/or its precursors from the extrahepatic tissues. L-SSKO mice showed a transient liver dysfunction with moderate hepatomegaly presumably secondary to increased farnesol production. In a fed state, the plasma total cholesterol and triglyceride were signifi cantly reduced in L-SSKO mice, primarily owing to reduced hepatic VLDL secretion. In a fasted state, the hypolipidemic effect was lost. mRNA expression of liver X receptor ␣ target genes was reduced, while that of sterol-regulatory element binding protein 2 target genes was increased. In conclusion, liver-specifi c ablation of SS inhibits hepatic cholesterol biosynthesis and induces hypolipidemia without increasing signifi cant mortality. -Nagashima, S

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Inhibition of squalene synthase upregulates PCSK9 expression in rat liver

Cited by 17 publications

References 18 publications

Regulation of the proprotein convertase subtilisin/kexin type 9 in intestinal epithelial cells

Regulation of the proprotein convertase subtilisin/kexin type 9 in intestinal epithelial cells

ABCC6- a new player in cellular cholesterol and lipoprotein metabolism?

Plasma cholesterol-lowering and transient liver dysfunction in mice lacking squalene synthase in the liver

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