A5071212381- Lipoproteins and Cardiovascular Health
- Cholesterol and Lipid Metabolism
- Protein Kinase Regulation and GTPase Signaling
- Cancer, Lipids, and Metabolism
- Hormonal Regulation and Hypertension
- Steroid Chemistry and Biochemistry
- Nuclear Receptors and Signaling
- RNA and protein synthesis mechanisms
- Cell Adhesion Molecules Research
- Peroxisome Proliferator-Activated Receptors
- Drug Transport and Resistance Mechanisms
- Genetic factors in colorectal cancer
- Diabetes, Cardiovascular Risks, and Lipoproteins
- Diabetes Treatment and Management
- RNA Research and Splicing
- Plant biochemistry and biosynthesis
- Cellular transport and secretion
- Neurological Disorders and Treatments
- Immune cells in cancer
- PARP inhibition in cancer therapy
- RNA regulation and disease
- Plant responses to water stress
- Receptor Mechanisms and Signaling
- Ion Transport and Channel Regulation
- Legionella and Acanthamoeba research
Humanitas University
2024-2025
IRCCS Humanitas Research Hospital
2024-2025
The University of Texas Southwestern Medical Center
2005-2013
Promega (United States)
2010
McDermott International (United States)
2008
Southwestern Medical Center
2006
University of Modena and Reggio Emilia
1993-2004
University of Sassari
2000
University of Genoa
1997-2000
University of Siena
1997
Proprotein convertase subtilisin/kexin type 9 (PCSK9) promotes degradation of hepatic low density lipoprotein receptors (LDLR), the major route clearance circulating cholesterol. Gain-of-function mutations in PCSK9 cause hypercholesterolemia and premature atherosclerosis, whereas loss-of-function result hypocholesterolemia protection from heart disease. Recombinant human binds LDLR on surface cultured hepatocytes receptor after internalization. Here we localized site binding within...
PCSK9 encodes proprotein convertase subtilisin/kexin type 9a (PCSK9), a member of the proteinase K subfamily subtilases. Missense mutations in cause an autosomal dominant form hypercholesterolemia humans, likely due to gain-of-function mechanism because overexpression either WT or mutant reduces hepatic LDL receptor protein (LDLR) mice. Here, we show that livers knockout mice lacking manifest increased LDLR but not mRNA. Increased led clearance circulating lipoproteins and decreased plasma...
Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a member of the proteinase K subfamily subtilases that reduces number LDL receptors (LDLRs) in liver through an undefined posttranscriptional mechanism. We show purified PCSK9 added to medium HepG2 cells cell-surface LDLRs dose- and time-dependent manner. This activity was approximately 10-fold greater for gain-of-function mutant, PCSK9(D374Y), causes hypercholesterolemia. Binding uptake were largely dependent on presence LDLRs....
Obesity and insulin resistance are associated with deposition of triglycerides in tissues other than adipose tissue. Previously, we showed that a missense mutation (I148M) PNPLA3 (patatin-like phospholipase domain-containing 3 protein) is increased hepatic triglyceride content humans. Here examined the effect I148M substitution on enzymatic activity cellular location PNPLA3. Structural modeling predicted methionine for isoleucine at residue 148 would restrict access substrate to catalytic...
Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a secreted protein that controls plasma LDL cholesterol levels by posttranslational regulation of the receptor (LDLR). Previously, we showed PCSK9 binds specifically to an EGF-like repeat (EGF-A) in LDLR and reroutes from endosomes lysosomes rather than cell surface. Here, defined regions are required for degradation examined relationship between binding conformation. Addition cultured hepatocytes promoted WT receptors lacking up four...
Cholesterol uptake and efflux are key metabolic processes associated with macrophage physiology atherosclerosis. Peroxisome proliferator-activated receptor gamma (PPARγ) liver X alpha (LXRα) have been linked to the regulation of these processes. It remains be identified how activation receptors is connected regulated by endogenous lipid molecules. We CYP27, a p450 enzyme, as link between retinoid, PPARγ, LXR signaling. show that human CYP27 gene under coupled retinoids ligands PPARs via...
Autosomal recessive hypercholesterolemia is characterized by a cell type-specific defect in low density lipoprotein receptor (LDLR) endocytosis. LDLR-mediated uptake of LDL impaired the liver, but not fibroblasts subjects with this disorder. The disease caused mutations ARH, which encodes putative adaptor protein that interacts cytoplasmic tail LDLR, phospholipids, and two components clathrin endocytic machinery, protein-2 (AP-2) vitro. To determine physiological relevance these...
Renal outer medullary potassium (ROMK) channels are exquisitely regulated to adjust renal excretion and maintain balance. Clathrin-dependent endocytosis plays a critical role, limiting urinary loss in deficiency. In disease, aberrant ROMK may contribute retention hyperkalemia. Previous work has indicated that is stimulated by with-no-lysine (WNK) kinases, but the endocytotic signal internalization machinery have not been defined. Here, we found bound directly clathrin adaptor molecule...
Genetic defects in LDL clearance result severe hypercholesterolemia and premature atherosclerosis. Mutations the receptor (LDLR) cause familial (FH), most form of genetic hypercholesterolemia. A phenocopy FH, autosomal recessive (ARH), is due to mutations an adaptor protein involved LDLR internalization. Despite comparable reductions rates, plasma levels are substantially lower ARH than FH. To determine metabolic basis for this difference, we examined synthesis catabolism VLDL murine models...
Abstract —The aim of this study was the characterization mutations LDL receptor gene in 39 Italian patients with homozygous familial hypercholesterolemia, who were examined during period 1994 to 1996. The age ranged from 1 64 years; one third them older than 30. Plasma cholesterol level 10.8 25.1 mmol/L. residual activity, measured cultured fibroblasts 32 patients, varied <2% 30% normal and inversely correlated plasma ( r =−0.665; P <0.003). most severe coronary atherosclerosis...
Cerebrotendinous xanthomatosis (CTX) is an inherited sterol storage disease associated with the accumulation of cholestanol and cholesterol in various tissues. CTX caused by a deficiency sterol-27-hydroxylase, mitochondrial enzyme that oxidizes side chain pathway leading to formation bile acids. In present study we report two mutations sterol-27-hydroxylase gene (CYP27 gene) found Italian patients. Proband T.C. homozygous for G-->A transition at first nucleotide intron 7. This mutation...
Abstract. Coronary heart disease is a prevalent condition and leading cause of death in developed countries. Most cases are due to the cluster classical risk factors, such as smoking, diabetes, high blood pressure dyslipidaemia. However, few patients develop severe premature arteriosclerosis spite absence common factors. Here, we present clinical, analytical molecular features 36‐years‐old man who died from advanced ischaemic result cerebrotendinous xanthomatosis (CTX), rare characterized by...
We report the characterization of eight mutations sterol 27-hydroxylase gene (CYP27) in five Italian patients with cerebrotendinous xanthomatosis, who were found to be compound heterozygotes.Four (C -+ T at nt 45
Two point mutations of ABCA1 gene were found in a patient with Tangier disease (TD): i) G>C intron 2 (IVS2 +5G>C) and ii) c.844 C>T exon 9 (R282X). The IVS2 +5G>C mutation was also the brother another deceased TD patient, but not 78 controls 33 subjects low HDL. disrupts pre-mRNA splicing fibroblasts, leading to three abnormal mRNAs: devoid (Ex2−/mRNA), 4 (Ex4−/mRNA), or both these exons (Ex2−/Ex4−/mRNA), each containing translation initiation site. These mRNAs are expected either be...
Abstract —One of the genetic features Sardinian population is high prevalence hemoglobin disorders. It has been estimated that 13% to 33% Sardinians carry a mutant allele α-globin gene (α-thalassemia trait) and 6% 17% are β-thalassemia carriers. In this population, single mutation β-globin (Q39X, β 0 39) accounts for >95% cases. Because previous studies have shown carriers lower total low density lipoprotein (LDL) cholesterol than noncarriers, we wondered whether LDL-lowering effect trait...
The LDL receptor (LDLR) relies upon endocytic adaptor proteins for internalization of lipoproteins. results this study show that the LDLR autosomal recessive hypercholesterolemia protein (ARH) requires nitric oxide to support uptake. Nitric nitrosylates ARH at C199 and C286, these posttranslational modifications are necessary association with 2 (AP-2) component clathrin-coated pits. In absence nitrosylation, is unable target LDL-LDLR complexes coated pits, resulting in poor role on function...
An Italian subject with cerebrotendinous xanthomatosis (CTX) was found to have a partial deletion of the gene encoding enzyme sterol 27-hydroxylase (CYP27 gene). Southern blot analysis revealed that this (approximately 2 kb) spans from intron 6 3' flanking (3'FLK) region, eliminating exons 7-9, last three CYP27 gene. No mRNA detected in proband cells, either by Northern or reverse transcription polymerase chain reaction (PCR). This suggests mutant devoid exon whole untranslated sequence...
Abstract In this study, we report four new partial deletions of the LDL-receptor (LDL-R) gene discovered during a survey 326 Italian patients with familial hypercholesterolemia (FH). All were found in FH heterozygotes whose LDL-R activity skin fibroblasts ranged from 52% to 43% values control cells. The size and boundaries defined by Southern blotting and, some cases, polymerase chain reaction (PCR) amplification genomic DNA. sequence deletion joint was performed after reverse transcription...
Mutations of the gene encoding mitochondrial enzyme sterol 27-hydroxylase (CYP27A1 gene) cause defects in cholesterol pathway to bile acids that lead storage cholestanol and tendons, lenses central nervous system. This disorder is a clinical syndrome known as cerebrotendinous xanthomatosis (CTX). Since 1991 several mutations CYP27A1 have been reported. We diagnosed features CTX caucasian woman. Serum levels 7α-hydroxycholesterol were elevated concentration 27-hydroxycholesterol was reduced....