Background The association between proprotein convertase subtilisin/kexin type 9 (PCSK9), a critical regulator of low-density lipoprotein (LDL) metabolism, and kidney function is a matter of debate. ...Objective We aimed to assess the association of circulating PCSK9 concentrations with both glomerular filtration rate (eGFR) and serum lipid parameters in nondiabetic patients with chronic kidney disease (CKD). Methods Fasting plasma PCSK9 concentrations were measured by ELISA in 94 nondiabetic nondialysis CKD (ND-CKD) patients not receiving statins, at different stages of CKD. Results Plasma PCSK9 levels were associated neither to eGFR ( P = .770) nor to proteinuria ( P = .888) at several stages of CKD. In addition, plasma PCSK9 levels did not vary significantly between the different CKD stages. Plasma PCSK9 concentrations were positively correlated with apolipoprotein B (r = 0.221; P = .03) and triglycerides (r = 0.211; P = .04) but not with total cholesterol, calculated LDL-cholesterol, HDL cholesterol, lipoprotein(a), or CRP. Conclusion In a homogeneous population of nondiabetic subjects without lipid-lowering therapy, plasma PCSK9 concentrations are not associated to eGFR at several stages of CKD. These data suggest that kidney function per se does not impact significantly PCSK9 metabolism.
Liver carnitine palmitoyl transferase (L-CPT) I is a key regulatory enzyme of long-chain fatty acid (LCFA) oxidation that ensures the first step of LCFA import into the mitochondrial matrix. In rat ...hepatocytes, we showed previously that L-CPT I gene expression was induced by LCFAs as well as by fibrates. The aim of this study was to determine whether LCFA-induced L-CPT I gene expression was mediated by PPARα. For this purpose, we constructed a PPARα-dominant negative receptor to inhibit endogenous PPARα signaling. Highly conserved hydrophobic and charged residues (Leu459 and Glu462) in helix 12 of the ligand-binding domain were mutated to alanine. These mutations led to a total loss of transcriptional activity due to impaired coactivator recruitment. Furthermore, competition studies confirmed that the mutated PPARα receptor abolished the wild-type PPARα receptor action and thus acted as a powerful dominant negative receptor. When overexpressed in rat hepatoma cells (H4IIE) using a recombinant adenovirus, the mutated PPARα receptor antagonized the clofibrate-induced L-CPT I gene expression, whereas it did not affect LCFA-induced L-CPT I. These results provide the first direct demonstration that LCFAs regulate L-CPT I transcription through a PPARα-independent pathway, at least in hepatoma cells.
The peroxisome proliferator-activated receptor alpha (PPARα) belongs to the nuclear receptor family and plays a central role in the regulation of lipid metabolism, glucose homeostasis and ...inflammatory processes. In addition to its ligand-induced activation, PPARα is regulated by phosphorylation
via ERK-MAPK, PKA and PKC. In this study we examined the effect of p38-MAPK on PPARα transcriptional activity. In COS-7 cells, anisomycin, a p38 activator, induced a dose-dependent phosphorylation of PPARα and a 50% inhibition of its transcriptional activity. In H4IIE hepatoma cells, anisomycin-induced p38 phosphorylation decreased both endogenous and PPARα ligand-enhanced L-CPTI and ACO gene expression. Interestingly, PPARα/p38 interaction required the molecular adapter ZIP/p62. Reducing ZIP/p62 expression by siRNA, partially reversed the inhibitory effect of anisomycin on L-CPTI gene expression. In conclusion, we showed that p38 activation induced PPARα phosphorylation and inhibition of its transcriptional activity through a trimeric interaction between p38-MAPK, ZIP/p62 and PPARα.
The study aims to assess the association between proprotein convertase subtilisin/kexin type 9 (PCSK9), a major regulator of LDL cholesterol (LDL-C) homeostasis, and HIV-related dyslipidaemia in a ...cohort of HIV-positive (HIV+) patients under protease inhibitors.
Plasma PCSK9 levels were measured in 103 HIV+ patients before and after initiating protease inhibitor-based antiretroviral therapy (ART), and in 90 HIV-negative controls matched for age and sex. PCSK9 was measured by ELISA. HIV+ patients who were not virologically suppressed at follow-up or were on lipid-lowering therapy were excluded.
In HIV+ (median age 36 years; 77.7% men), PCSK9 levels did not increase after protease inhibitor exposure (median 14 months) (279.5 ng/ml before, 289.6 ng/ml after; P = 0.49) and were significantly elevated versus controls at all timepoints (adjusted P value before and after: <0.05). After protease inhibitor initiation, total cholesterol, LDL-C and HDL cholesterol levels increased, but LDL-C remained lower versus controls. At baseline, PCSK9 levels were positively associated with immunodeficiency and the severity of HIV disease HIV-1 viral load (P = 0.01), CD4 T-cell count <200/μl, P = 0.002, stage C HIV disease (P = 0.0002). In protease inhibitor-treated patients, PCSK9 levels were no longer associated with HIV-related factors but with total cholesterol (P = 0.0006), LDL-C (P = 0.01), HDL cholesterol (P = 0.01), triglycerides (P = 0.05) and glycaemia (P = 0.006).
PSCK9 levels are elevated in HIV+ patients. In ART-naive patients, the relationship between PCSK9 levels and infection severity suggests an effect of HIV disease. After initiating protease inhibitor-containing ART in virologically suppressed patients, PCSK9 levels were associated with dyslipidaemia similar to controls.
Glucose and fatty acid metabolism (oxidation versus esterification) has been measured in hepatocytes isolated from 24 h starved peroxisome proliferator-activated receptor-α (PPARα) null and wild-type ...mice. In PPARα null mice, the development of hypoglycemia during starvation was due to a reduced capacity for hepatic gluconeogenesis secondary to a 70% lower rate of fatty acid oxidation. This was not due to inappropriate expression of the hepatic CPT I gene, which was similar in both genotypes, but to impaired mitochondrial hydroxymethylglutaryl-CoA synthase gene expression in the PPARα null mouse liver. We also demonstrate that hepatic steatosis of fasting PPARα null mice was not due to enhanced triglyceride synthesis.
PCSK9 inhibition protects mice from food allergy Lorant, Victoria; Klein, Martin; Garçon, Damien ...
Translational research : the journal of laboratory and clinical medicine,
October 2024, Letnik:
272
Journal Article
Recenzirano
Odprti dostop
The Proprotein Convertase Subtilisin Kexin of type 9 (PCSK9) has been identified in 2003 as the third gene involved in familial hypercholesterolemia. PCSK9 binds to the membrane low-density ...lipoprotein receptor (LDLR) and promotes its cellular internalization and lysosomal degradation. Beyond this canonical role, PCSK9 was recently described to be involved in several immune responses. However, to date, the contribution of PCSK9 in food allergy remains unknown. Here, we showed that Pcsk9 deficiency or pharmacological inhibition of circulating PCSK9 with a specific monoclonal antibody (m-Ab) protected mice against symptoms of gliadin-induced-food allergy, such as increased intestinal transit time and ear oedema. Furthermore, specific PCSK9 inhibition during the elicitation steps of allergic process was sufficient to ensure anti-allergic effects in mice. Interestingly, the protective effect of PCSK9 inhibition against food allergy symptoms was independent of the LDLR as PCSK9 inhibitors remained effective in Ldlr deficient mice. In vitro, we showed that recombinant gain of function PCSK9 (PCSK9 D374Y) increased the percentage of mature bone marrow derived dendritic cells (BMDCs), promoted naïve T cell proliferation and potentiated the gliadin induced basophils degranulation. Altogether, our data demonstrate that PCSK9 inhibition is protective against gliadin induced food allergy in a LDLR-independent manner.
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