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1.
J Biol Chem ; 298(6): 101936, 2022 06.
Artículo en Inglés | MEDLINE | ID: mdl-35430252

RESUMEN

Valosin-containing protein (VCP) is a member of AAA-ATPase superfamily involved in various cellular functions. To investigate the pathophysiological role of VCP in metabolic disorders, we generated knock-in mice bearing an A232E mutation in VCP, a known human VCP pathogenic variant. When heterozygous mutant mice (A232E/+) were fed a high-fat diet, we observed that fatty liver was ameliorated and the proteolytic processing of the transcription factor sterol regulatory element-binding protein 1 (SREBP1) was impaired. Further co-immunoprecipitation analysis in wildtype mice revealed interactions of VCP with SREBP1 and a rhomboid protease, RHBDL4, in the liver, and these interactions were attenuated in A232E/+ mice. Consistent with these results, we show that knockdown or chemical inhibition of VCP or RHBDL4 in human hepatocytes impaired the proteolytic processing of SREBP1. Finally, we found that knockdown of E3 ligases such as glycoprotein 78 and HMG-CoA reductase degradation protein 1 disrupted the interaction of VCP with SREBP1 and impaired the proteolytic processing of SREBP1. These results suggest that VCP recognizes ubiquitinylated SREBP1 and recruits it to RHBDL4 to promote its proteolytic processing. The present study reveals a novel proteolytic processing pathway of SREBP1 and may lead to development of new therapeutic strategies to treat fatty liver diseases.


Asunto(s)
Proteínas de la Membrana , Proteína 1 de Unión a los Elementos Reguladores de Esteroles , Proteína que Contiene Valosina , Adenosina Trifosfatasas/metabolismo , Animales , Proteínas de la Membrana/metabolismo , Ratones , Enfermedad del Hígado Graso no Alcohólico/fisiopatología , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/genética , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/metabolismo , Proteína que Contiene Valosina/genética , Proteína que Contiene Valosina/metabolismo
2.
J Biol Chem ; 298(9): 102322, 2022 09.
Artículo en Inglés | MEDLINE | ID: mdl-35926714

RESUMEN

During obesity, tissue macrophages increase in number and become proinflammatory, thereby contributing to metabolic dysfunction. Lipoprotein lipase (LPL), which hydrolyzes triglyceride in lipoproteins, is secreted by macrophages. However, the role of macrophage-derived LPL in adipose tissue remodeling and lipoprotein metabolism is largely unknown. To clarify these issues, we crossed leptin-deficient Lepob/ob mice with mice lacking the Lpl gene in myeloid cells (Lplm-/m-) to generate Lplm-/m-;Lepob/ob mice. We found the weight of perigonadal white adipose tissue (WAT) was increased in Lplm-/m-;Lepob/ob mice compared with Lepob/ob mice due to substantial accumulation of both adipose tissue macrophages and collagen that surrounded necrotic adipocytes. In the fibrotic epidydimal WAT of Lplm-/m-;Lepob/ob mice, we observed an increase in collagen VI and high mobility group box 1, while α-smooth muscle cell actin, a marker of myofibroblasts, was almost undetectable, suggesting that the adipocytes were the major source of the collagens. Furthermore, the adipose tissue macrophages from Lplm-/m-;Lepob/ob mice showed increased expression of genes related to fibrosis and inflammation. In addition, we determined Lplm-/m-;Lepob/ob mice were more hypertriglyceridemic than Lepob/ob mice. Lplm-/m-;Lepob/ob mice also showed slower weight gain than Lepob/ob mice, which was primarily due to reduced food intake. In conclusion, we discovered that the loss of myeloid Lpl led to extensive fibrosis of perigonadal WAT and hypertriglyceridemia. In addition to illustrating an important role of macrophage LPL in regulation of circulating triglyceride levels, these data show that macrophage LPL protects against fibrosis in obese adipose tissues.


Asunto(s)
Tejido Adiposo Blanco , Colágeno Tipo IV , Hipertrigliceridemia , Lipoproteína Lipasa , Obesidad , Actinas/metabolismo , Tejido Adiposo Blanco/patología , Animales , Colágeno Tipo IV/metabolismo , Fibrosis , Hipertrigliceridemia/genética , Hipertrigliceridemia/patología , Leptina/deficiencia , Leptina/genética , Lipoproteína Lipasa/genética , Lipoproteínas/metabolismo , Ratones , Ratones Obesos , Obesidad/genética , Obesidad/metabolismo , Obesidad/patología , Triglicéridos/sangre
3.
Cardiol Young ; 33(3): 493-495, 2023 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-35801280

RESUMEN

The Chiari network is an embryonic remnant of the right venosus, consisting of a thin, mobile structure connected to the right atrium. Neonates with the Chiari network may present with hypoxemia. We report a case of a neonate with persistent hypoxemia despite improvement in respiratory distress symptoms and increased supplemental oxygen that was diagnosed using real-time telemedicine.


Asunto(s)
Ecocardiografía , Cardiopatías Congénitas , Recién Nacido , Humanos , Cardiopatías Congénitas/diagnóstico , Atrios Cardíacos/diagnóstico por imagen , Diagnóstico Diferencial , Hipoxia/diagnóstico , Hipoxia/etiología
4.
J Lipid Res ; 61(9): 1287-1299, 2020 09.
Artículo en Inglés | MEDLINE | ID: mdl-32561542

RESUMEN

The acyltransferase LCAT mediates FA esterification of plasma cholesterol. In vitro studies have shown that LCAT also FA-esterifies several oxysterols, but in vivo evidence is lacking. Here, we measured both free and FA-esterified forms of sterols in 206 healthy volunteers and 8 individuals with genetic LCAT deficiency, including familial LCAT deficiency (FLD) and fish-eye disease (FED). In the healthy volunteers, the mean values of the ester-to-total molar ratios of the following sterols varied: 4ß-hydroxycholesterol (4ßHC), 0.38; 5,6α-epoxycholesterol (5,6αEC), 0.46; 5,6ß-epoxycholesterol (5,6ßEC), 0.51; cholesterol, 0.70; cholestane-3ß,5α,6ß-triol (CT), 0.70; 7-ketocholesterol (7KC), 0.75; 24S-hydroxycholesterol (24SHC), 0.80; 25-hydroxycholesterol (25HC), 0.81; 27-hydroxycholesterol (27HC), 0.86; and 7α-hydroxycholesterol (7αHC), 0.89. In the individuals with LCAT deficiency, the plasma levels of the FA-esterified forms of cholesterol, 5,6αEC, 5,6ßEC, CT, 7αHC, 7KC, 24SHC, 25HC, and 27HC, were significantly lower than those in the healthy volunteers. The individuals with FLD had significantly lower FA-esterified forms of 7αHC, 24SHC, and 27HC than those with FED. It is of note that, even in the three FLD individuals with negligible plasma cholesteryl ester, substantial amounts of the FA-esterified forms of 4ßHC, 5,6αEC, 7αHC, 7KC, and 27HC were present. We conclude that LCAT has a major role in the FA esterification of many plasma oxysterols but contributes little to the FA esterification of 4ßHC. Substantial FA esterification of 4ßHC, 5,6αEC, 7αHC, 7KC, and 27HC is independent of LCAT.


Asunto(s)
Hidroxicolesteroles/sangre , Hidroxicolesteroles/metabolismo , Fosfatidilcolina-Esterol O-Aciltransferasa/metabolismo , Adulto , Estudios de Casos y Controles , Esterificación , Femenino , Humanos , Masculino , Fosfatidilcolina-Esterol O-Aciltransferasa/genética , Adulto Joven
5.
Arterioscler Thromb Vasc Biol ; 39(3): 373-386, 2019 03.
Artículo en Inglés | MEDLINE | ID: mdl-30700132

RESUMEN

Objective- APOA5 variants are strongly associated with hypertriglyceridemia, as well as increased risks of cardiovascular disease and acute pancreatitis. Hypertriglyceridemia in apo AV dysfunction often aggravates by environmental factors such as high-carbohydrate diets or aging. To date, the molecular mechanisms by which these environmental factors induce hypertriglyceridemia are poorly defined, leaving the high-risk hypertriglyceridemia condition undertreated. Previously, we reported that LXR (liver X receptor)-SREBP (sterol regulatory element-binding protein)-1c pathway regulates large-VLDL (very low-density lipoprotein) production induced by LXR agonist. However, the pathophysiological relevance of the finding remains unknown. Approach and Results- Here, we reconstitute the environment-induced hypertriglyceridemia phenotype of human APOA5 deficiency in Apoa5-/- mice and delineate the role of SREBP-1c in vivo by generating Apoa5-/- ;Srebp-1c-/- mice. The Apoa5-/- mice, which showed moderate hypertriglyceridemia on a chow diet, developed severe hypertriglyceridemia on high-carbohydrate feeding or aging as seen in patients with human apo AV deficiency. These responses were nearly completely abolished in the Apoa5-/- ;Srebp-1c-/- mice. Further mechanistic studies revealed that in response to these environmental factors, SREBP-1c was activated to increase triglyceride synthesis and to permit the incorporation of triglyceride into abnormally large-VLDL particles, which require apo AV for efficient clearance. Conclusions- Severe hypertriglyceridemia develops only when genetic factors (apo AV deficiency) and environmental effects (SREBP-1c activation) coexist. We demonstrate that the regulated production of large-sized VLDL particles via SREBP-1c determines plasma triglyceride levels in apo AV deficiency. Our findings explain the long-standing enigma of the late-onset hypertriglyceridemia phenotype of apo AV deficiency and suggest a new approach to treat hypertriglyceridemia by targeting genes that mediate environmental effects.


Asunto(s)
Apolipoproteína A-V/deficiencia , Hipertrigliceridemia/sangre , Lipoproteínas VLDL/biosíntesis , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/fisiología , Envejecimiento/metabolismo , Alimentación Animal/efectos adversos , Animales , Apolipoproteína A-V/genética , Apolipoproteínas/sangre , Quilomicrones/metabolismo , Femenino , Fructosa/toxicidad , Regulación de la Expresión Génica/efectos de los fármacos , Interacción Gen-Ambiente , Humanos , Hidrocarburos Fluorados/farmacología , Hipertrigliceridemia/inducido químicamente , Hipertrigliceridemia/genética , Lípidos/sangre , Receptores X del Hígado/agonistas , Receptores X del Hígado/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Modelos Animales , Aceite de Oliva/toxicidad , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/deficiencia , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/genética , Sulfonamidas/farmacología
6.
J Infect Chemother ; 26(9): 873-881, 2020 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-32565151

RESUMEN

The nationwide surveillance on antimicrobial susceptibility of bacterial respiratory pathogens from the patients in Japan was conducted by the Japanese Society of Chemotherapy, the Japanese Association for Infectious Diseases, and the Japanese Society for Clinical Microbiology in 2016. The isolates were collected from clinical specimens obtained from well-diagnosed adult patients with respiratory tract infections during the period between February 2016 and August 2016 by three societies. Antimicrobial susceptibility testing was conducted at the central reference laboratory according to the method recommended by Clinical Laboratory Standards Institute. Susceptibility testing was evaluated in 1062 strains (143 Staphylococcus aureus, 210 Streptococcus pneumoniae, 17 Streptococcus pyogenes, 248 Haemophilus influenzae, 151 Moraxella catarrhalis, 134 Klebsiella pneumoniae, and 159 Pseudomonas aeruginosa). Ratio of methicillin-resistant S. aureus was 48.3%, and those of penicillin-susceptible S. pneumoniae was 99.5%. Among H. influenzae, 14.1% of them were found to be ß-lactamase-producing ampicillin-resistant strains, and 41.1% to be ß-lactamase-non-producing ampicillin-resistant strains. Extended spectrum ß-lactamase-producing K. pneumoniae and multi-drug resistant P. aeruginosa with metallo ß-lactamase were 4.5% and 0.6%, respectively.


Asunto(s)
Enfermedades Transmisibles , Staphylococcus aureus Resistente a Meticilina , Infecciones del Sistema Respiratorio , Adulto , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Enfermedades Transmisibles/tratamiento farmacológico , Farmacorresistencia Bacteriana , Haemophilus influenzae , Humanos , Japón/epidemiología , Pruebas de Sensibilidad Microbiana , Infecciones del Sistema Respiratorio/tratamiento farmacológico , Infecciones del Sistema Respiratorio/epidemiología
7.
Arterioscler Thromb Vasc Biol ; 38(11): 2576-2589, 2018 11.
Artículo en Inglés | MEDLINE | ID: mdl-30354239

RESUMEN

Objective- ACAT1 (Acyl-CoA cholesterol acyltransferase 1) esterifies cellular free cholesterol, thereby converting macrophages to cholesteryl ester-laden foam cells in atherosclerotic lesions and cutaneous xanthoma. Paradoxically, however, loss of ACAT1 in bone marrow causes the aggravation of atherosclerosis and the development of severe cutaneous xanthoma in hyperlipidemic mice. Recently, it has been reported that cholesterol crystals activate NLRP3 (NACHT, LRR [leucine-rich repeats], and PYD [pyrin domain] domain-containing protein 3) inflammasomes, thereby contributing to the development of atherosclerosis. The present study aimed to clarify the role of NLRP3 inflammasomes in the worsening of atherosclerosis and cutaneous xanthoma induced by ACAT1 deficiency. Approach and Results- Ldlr-null mice were transplanted with bone marrow from WT (wild type) mice and mice lacking ACAT1, NLRP3, or both. After the 4 types of mice were fed high-cholesterol diets, we compared their atherosclerosis and skin lesions. The mice transplanted with Acat1-null bone marrow developed severe cutaneous xanthoma, which was filled with numerous macrophages and cholesterol clefts and had markedly increased expression of inflammatory cytokines, and increased atherosclerosis. Loss of NLRP3 completely reversed the cutaneous xanthoma, whereas it improved the atherosclerosis only partially. Acat1-null peritoneal macrophages showed enhanced expression of CHOP (C/EBP [CCAAT/enhancer binding protein] homologous protein) and TNF-α (tumor necrosis factor-α) but no evidence of inflammasome activation, after treatment with acetylated LDL (low-density lipoprotein). Conclusions- Elimination of ACAT1 in bone marrow-derived cells aggravates cutaneous xanthoma and atherosclerosis. The development of cutaneous xanthoma is induced mainly via the NLRP3 inflammasome activation.


Asunto(s)
Acetil-CoA C-Acetiltransferasa/metabolismo , Enfermedades de la Aorta/enzimología , Aterosclerosis/enzimología , Médula Ósea/enzimología , Inflamasomas/metabolismo , Macrófagos Peritoneales/enzimología , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Placa Aterosclerótica , Enfermedades de la Piel/enzimología , Xantomatosis/enzimología , Acetil-CoA C-Acetiltransferasa/deficiencia , Acetil-CoA C-Acetiltransferasa/genética , Animales , Enfermedades de la Aorta/genética , Enfermedades de la Aorta/patología , Enfermedades de la Aorta/prevención & control , Aterosclerosis/genética , Aterosclerosis/patología , Aterosclerosis/prevención & control , Médula Ósea/patología , Trasplante de Médula Ósea , Células Cultivadas , Colesterol en la Dieta , Modelos Animales de Enfermedad , Femenino , Predisposición Genética a la Enfermedad , Macrófagos Peritoneales/patología , Ratones Endogámicos C57BL , Ratones Noqueados , Proteína con Dominio Pirina 3 de la Familia NLR/deficiencia , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Fenotipo , Receptores de LDL/genética , Receptores de LDL/metabolismo , Transducción de Señal , Enfermedades de la Piel/genética , Enfermedades de la Piel/patología , Enfermedades de la Piel/prevención & control , Xantomatosis/genética , Xantomatosis/patología , Xantomatosis/prevención & control
8.
Arterioscler Thromb Vasc Biol ; 38(11): 2590-2600, 2018 11.
Artículo en Inglés | MEDLINE | ID: mdl-30354246

RESUMEN

Objective- Inhibition of HMGCR (3-hydroxy-3-methylglutaryl-coenzyme A reductase) is atheroprotective primarily by decreasing plasma LDL (low-density lipoprotein)-cholesterol. However, it is unknown whether inhibition of HMGCR in myeloid cells contributes to this atheroprotection. We sought to determine the role of myeloid HMGCR in the development of atherosclerosis. Approach and Results- We generated mice with genetically reduced Hmgcr in myeloid cells ( Hmgcr m-/m-) using LysM (Cre) and compared various functions of their macrophages to those of Hmgcr fl/fl control mice. We further compared the extent of atherosclerosis in Hmgcr m-/ m- and Hmgcr fl/fl mice in the absence of Ldlr (LDL receptor). Hmgcr m-/ m- macrophages and granulocytes had significantly lower Hmgcr mRNA expression and cholesterol biosynthesis than Hmgcr fl/fl cells. In vitro, Hmgcr m-/ m- monocytes/macrophages had reduced ability to migrate, proliferate, and survive compared with Hmgcr fl/fl monocytes/macrophages. However, there was no difference in ability to adhere, phagocytose, store lipids, or polarize to M1 macrophages between the 2 types of macrophages. The amounts of plasma membrane-associated small GTPase proteins, such as RhoA (RAS homolog family member A), were increased in Hmgcr m-/ m- macrophages. In the setting of Ldlr deficiency, Hmgcr m-/ m- mice developed significantly smaller atherosclerotic lesions than Hmgcr fl/fl mice. However, there were no differences between the 2 types of mice either in plasma lipoprotein profiles or in the numbers of proliferating or apoptotic cells in the lesions in vivo. The in vivo migration of Hmgcr m-/ m- macrophages to the lesions was reduced compared with Hmgcr fl/fl macrophages. Conclusions- Genetic reduction of HMGCR in myeloid cells may exert atheroprotective effects primarily by decreasing the migratory activity of monocytes/macrophages to the lesions.


Asunto(s)
Aorta/enzimología , Enfermedades de la Aorta/enzimología , Aterosclerosis/enzimología , Movimiento Celular , Hidroximetilglutaril-CoA Reductasas/metabolismo , Macrófagos Peritoneales/enzimología , Monocitos/enzimología , Traslado Adoptivo , Animales , Aorta/patología , Enfermedades de la Aorta/genética , Enfermedades de la Aorta/patología , Enfermedades de la Aorta/prevención & control , Aterosclerosis/genética , Aterosclerosis/patología , Aterosclerosis/prevención & control , Proliferación Celular , Supervivencia Celular , Células Cultivadas , Modelos Animales de Enfermedad , Femenino , Predisposición Genética a la Enfermedad , Hidroximetilglutaril-CoA Reductasas/genética , Lípidos/sangre , Macrófagos Peritoneales/patología , Macrófagos Peritoneales/trasplante , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Monocitos/patología , Proteínas de Unión al GTP Monoméricas/metabolismo , Fenotipo , Receptores de LDL/deficiencia , Receptores de LDL/genética , Transducción de Señal
9.
J Infect Chemother ; 25(9): 657-668, 2019 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-31196772

RESUMEN

The nationwide surveillance on antimicrobial susceptibility of bacterial respiratory pathogens from the patients in Japan was conducted by Japanese Society of Chemotherapy, the Japanese Association for Infectious Diseases, and the Japanese Society for Clinical Microbiology in 2014. The isolates were collected from clinical specimens obtained from well-diagnosed adult patients with respiratory tract infections during the period between January 2014 and April 2015 by three societies. Antimicrobial susceptibility testing was conducted at the central reference laboratory according to the method recommended by Clinical Laboratory Standards Institute. Susceptibility testing was evaluated in 1534 strains (335 Staphylococcus aureus, 264 Streptococcus pneumoniae, 29 Streptococcus pyogenes, 281 Haemophilus influenzae, 164 Moraxella catarrhalis, 207 Klebsiella pneumoniae, and 254 Pseudomonas aeruginosa). Ratio of methicillin-resistant S. aureus was 43.6%, and those of penicillin-susceptible S. pneumoniae was 100%. Among H. influenzae, 8.2% of them were found to be ß-lactamase-producing ampicillin-resistant strains, and 49.1% to be ß-lactamase-non-producing ampicillin-resistant strains. Extended spectrum ß-lactamase-producing K. pneumoniae and multi-drug resistant P. aeruginosa with metallo ß-lactamase were 9.2% and 0.4%, respectively.


Asunto(s)
Antibacterianos/uso terapéutico , Farmacorresistencia Bacteriana , Monitoreo Epidemiológico , Infecciones del Sistema Respiratorio/prevención & control , Programas de Optimización del Uso de los Antimicrobianos , Haemophilus influenzae/efectos de los fármacos , Humanos , Japón/epidemiología , Klebsiella pneumoniae/efectos de los fármacos , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Pruebas de Sensibilidad Microbiana , Moraxella catarrhalis/efectos de los fármacos , Pseudomonas aeruginosa/efectos de los fármacos , Infecciones del Sistema Respiratorio/microbiología , Streptococcus pneumoniae/efectos de los fármacos , Streptococcus pyogenes/efectos de los fármacos
10.
J Infect Chemother ; 23(9): 587-597, 2017 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-28669567

RESUMEN

The nationwide surveillance on antimicrobial susceptibility of bacterial respiratory pathogens from the patients in Japan was conducted by Japanese Society of Chemotherapy, Japanese association for infectious diseases and Japanese society for Clinical Microbiology in 2012. The isolates were collected from clinical specimens obtained from well-diagnosed adult patients with respiratory tract infections during the period between January and December in 2012 by three societies. Antimicrobial susceptibility testing was conducted at the central reference laboratory according to the method recommended by Clinical Laboratory Standard Institutes. Susceptibility testing was evaluated in 1236 strains (232 Staphylococcus aureus, 225 Streptococcus pneumoniae, 16 Streptococcus pyogenes, 231 Haemophilus influenzae, 147 Moraxella catarrhalis, 167 Klebsiella pneumoniae and 218 Pseudomonas aeruginosa). Ratio of methicillin-resistant S. aureus was 51.3%, and those of penicillin-intermediate S. pneumoniae was 0.4%. Among H. influenzae, 5.6% of them were found to be ß-lactamase-producing ampicillin-resistant strains, and 37.2% to be ß-lactamase-non-producing ampicillin-resistant strains. Extended spectrum ß-lactamase-producing K. pneumoniae and multi-drug resistant P. aeruginosa with metallo ß-lactamase were 4.2% and 3.2%, respectively. Continuous national surveillance is important to determine the actual situation of the resistance shown by bacterial respiratory pathogens to antimicrobial agents.


Asunto(s)
Antibacterianos/farmacología , Bacterias/efectos de los fármacos , Bacterias/aislamiento & purificación , Sistema Respiratorio/microbiología , Infecciones del Sistema Respiratorio/microbiología , Farmacorresistencia Bacteriana , Haemophilus influenzae/efectos de los fármacos , Haemophilus influenzae/aislamiento & purificación , Humanos , Japón , Klebsiella pneumoniae/efectos de los fármacos , Klebsiella pneumoniae/aislamiento & purificación , Pruebas de Sensibilidad Microbiana , Moraxella catarrhalis/efectos de los fármacos , Moraxella catarrhalis/aislamiento & purificación , Pseudomonas aeruginosa/efectos de los fármacos , Pseudomonas aeruginosa/aislamiento & purificación , Vigilancia en Salud Pública , Staphylococcus aureus/efectos de los fármacos , Staphylococcus aureus/aislamiento & purificación , Streptococcus pneumoniae/efectos de los fármacos , Streptococcus pneumoniae/aislamiento & purificación , Streptococcus pyogenes/efectos de los fármacos , Streptococcus pyogenes/aislamiento & purificación , beta-Lactamasas/análisis
11.
J Lipid Res ; 56(5): 998-1005, 2015 May.
Artículo en Inglés | MEDLINE | ID: mdl-25755092

RESUMEN

Squalene synthase (SS) catalyzes the biosynthesis of squalene, the first specific 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 specifically 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 sufficient centripetal flow 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 significantly 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 α target genes was reduced, while that of sterol-regulatory element binding protein 2 target genes was increased. In conclusion, liver-specific ablation of SS inhibits hepatic cholesterol biosynthesis and induces hypolipidemia without increasing significant mortality.


Asunto(s)
Colesterol/sangre , Farnesil Difosfato Farnesil Transferasa/genética , Hígado/enzimología , Animales , Vías Biosintéticas , Colesterol/biosíntesis , Farnesil Difosfato Farnesil Transferasa/metabolismo , Hidroximetilglutaril-CoA Reductasas/metabolismo , Hígado/fisiopatología , Masculino , Ratones Transgénicos
12.
J Lipid Res ; 55(10): 2033-40, 2014 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-24868095

RESUMEN

Hydrolysis of intracellular cholesteryl ester (CE) is the rate-limiting step in the efflux of cholesterol from macrophage foam cells. In mouse peritoneal macrophages (MPMs), this process is thought to involve several enzymes: hormone-sensitive lipase (Lipe), carboxylesterase 3 (Ces3), neutral CE hydrolase 1 (Nceh1). However, there is some disagreement over the relative contributions of these enzymes. To solve this problem, we first compared the abilities of several compounds to inhibit the hydrolysis of CE in cells overexpressing Lipe, Ces3, or Nceh1. Cells overexpressing Ces3 had negligible neutral CE hydrolase activity. We next examined the effects of these inhibitors on the hydrolysis of CE and subsequent cholesterol trafficking in MPMs. CE accumulation was increased by a selective inhibitor of Nceh1, paraoxon, and two nonselective inhibitors of Nceh1, (+)-AS115 and (-)-AS115, but not by two Lipe-selective inhibitors, orlistat and 76-0079. Paraoxon inhibited cholesterol efflux to apoA-I or HDL, while 76-0079 did not. These results suggest that Nceh1 plays a dominant role over Lipe in the hydrolysis of CE and subsequent cholesterol efflux in MPMs.


Asunto(s)
Ésteres del Colesterol/metabolismo , Macrófagos Peritoneales/enzimología , Esterol Esterasa/metabolismo , Animales , Transporte Biológico Activo/efectos de los fármacos , Transporte Biológico Activo/genética , Carboxilesterasa/genética , Carboxilesterasa/metabolismo , Ésteres del Colesterol/genética , Inhibidores Enzimáticos/farmacología , Células HEK293 , Humanos , Hidrólisis , Ratones , Ratones Noqueados , Esterol Esterasa/antagonistas & inhibidores , Esterol Esterasa/genética
13.
J Lipid Res ; 55(10): 2082-92, 2014 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-24891333

RESUMEN

An excess of cholesterol and/or oxysterols induces apoptosis in macrophages, contributing to the development of advanced atherosclerotic lesions. In foam cells, these sterols are stored in esterified forms, which are hydrolyzed by two enzymes: neutral cholesterol ester hydrolase 1 (Nceh1) and hormone-sensitive lipase (Lipe). A deficiency in either enzyme leads to accelerated growth of atherosclerotic lesions in mice. However, it is poorly understood how the esterification and hydrolysis of sterols are linked to apoptosis. Remarkably, Nceh1-deficient thioglycollate-elicited peritoneal macrophages (TGEMs), but not Lipe-deficient TGEMs, were more susceptible to apoptosis induced by oxysterols, particularly 25-hydroxycholesterol (25-HC), and incubation with 25-HC caused massive accumulation of 25-HC ester in the endoplasmic reticulum (ER) due to its defective hydrolysis, thereby activating ER stress signaling such as induction of CCAAT/enhancer-binding protein-homologous protein (CHOP). These changes were nearly reversed by inhibition of ACAT1. In conclusion, deficiency of Nceh1 augments 25-HC-induced ER stress and subsequent apoptosis in TGEMs. In addition to reducing the cholesteryl ester content of foam cells, Nceh1 may protect against the pro-apoptotic effect of oxysterols and modulate the development of atherosclerosis.


Asunto(s)
Apoptosis , Estrés del Retículo Endoplásmico , Hidroxicolesteroles/metabolismo , Macrófagos Peritoneales/enzimología , Transducción de Señal , Esterol Esterasa/metabolismo , Acetil-CoA C-Acetiltransferasa/genética , Acetil-CoA C-Acetiltransferasa/metabolismo , Animales , Aterosclerosis/enzimología , Aterosclerosis/genética , Aterosclerosis/patología , Retículo Endoplásmico/enzimología , Retículo Endoplásmico/patología , Macrófagos Peritoneales/patología , Ratones , Ratones Noqueados , Esterol Esterasa/genética , Factor de Transcripción CHOP/genética , Factor de Transcripción CHOP/metabolismo
14.
J Biol Chem ; 288(20): 14046-14058, 2013 May 17.
Artículo en Inglés | MEDLINE | ID: mdl-23542081

RESUMEN

Adipose fat storage is thought to require uptake of circulating triglyceride (TG)-derived fatty acids via lipoprotein lipase (LpL). To determine how LpL affects the biology of adipose tissue, we created adipose-specific LpL knock-out (ATLO) mice, and we compared them with whole body LpL knock-out mice rescued with muscle LpL expression (MCK/L0) and wild type (WT) mice. ATLO LpL mRNA and activity were reduced, respectively, 75 and 70% in gonadal adipose tissue (GAT), 90 and 80% in subcutaneous tissue, and 84 and 85% in brown adipose tissue (BAT). ATLO mice had increased plasma TG levels associated with reduced chylomicron TG uptake into BAT and lung. ATLO BAT, but not GAT, had altered TG composition. GAT from MCK/L0 was smaller and contained less polyunsaturated fatty acids in TG, although GAT from ATLO was normal unless LpL was overexpressed in muscle. High fat diet feeding led to less adipose in MCK/L0 mice but TG acyl composition in subcutaneous tissue and BAT reverted to that of WT. Therefore, adipocyte LpL in BAT modulates plasma lipoprotein clearance, and the greater metabolic activity of this depot makes its lipid composition more dependent on LpL-mediated uptake. Loss of adipose LpL reduces fat accumulation only if accompanied by greater LpL activity in muscle. These data support the role of LpL as the "gatekeeper" for tissue lipid distribution.


Asunto(s)
Tejido Adiposo Pardo/metabolismo , Tejido Adiposo Blanco/metabolismo , Tejido Adiposo/metabolismo , Lipoproteína Lipasa/deficiencia , Lipoproteína Lipasa/genética , Adipocitos/citología , Animales , Trasplante de Médula Ósea , Quilomicrones/farmacocinética , Lípidos/química , Lipólisis , Macrófagos/citología , Masculino , Ratones , Ratones Noqueados , Fenotipo , Triglicéridos/sangre , Triglicéridos/metabolismo
15.
J Atheroscler Thromb ; 31(7): 1005-1023, 2024 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-38710625

RESUMEN

Familial hypobetalipoproteinemia (FHBL) 1 is a rare genetic disorder with an autosomal codominant mode of inheritance and is caused by defects in the apolipoprotein (apo) B (APOB) gene that disable lipoprotein formation. ApoB proteins are required for the formation of very low-density lipoproteins (VLDLs), chylomicrons, and their metabolites. VLDLs transport cholesterol and triglycerides from the liver to the peripheral tissues, whereas chylomicrons transport absorbed lipids and fat-soluble vitamins from the intestine. Homozygous or compound heterozygotes of FHBL1 (HoFHBL1) are extremely rare, and defects in APOB impair VLDL and chylomicron secretion, which result in marked hypolipidemia with malabsorption of fat and fat-soluble vitamins, leading to various complications such as growth disorders, acanthocytosis, retinitis pigmentosa, and neuropathy. Heterozygotes of FHBL1 are relatively common and are generally asymptomatic, except for moderate hypolipidemia and possible hepatic steatosis. If left untreated, HoFHBL1 can cause severe complications and disabilities that are pathologically and phenotypically similar to abetalipoproteinemia (ABL) (an autosomal recessive disorder) caused by mutations in the microsomal triglyceride transfer protein (MTTP) gene. Although HoFHBL1 and ABL cannot be distinguished from the clinical manifestations and laboratory findings of the proband, moderate hypolipidemia in first-degree relatives may help diagnose HoFHBL1. There is currently no specific treatment for HoFHBL1. Palliative therapy including high-dose fat-soluble vitamin supplementation may prevent or delay complications. Registry research on HoFHBL1 is currently ongoing to better understand the disease burden and unmet needs of this life-threatening disease with few therapeutic options.


Asunto(s)
Hipobetalipoproteinemias , Humanos , Hipobetalipoproteinemias/diagnóstico , Hipobetalipoproteinemias/genética , Hipobetalipoproteinemias/terapia , Manejo de la Enfermedad , Hipobetalipoproteinemia Familiar por Apolipoproteína B
16.
J Lipid Res ; 54(4): 1124-34, 2013 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-23378601

RESUMEN

The role of macrophage lipoprotein lipase (LpL) in the development of atherosclerosis and adiposity was examined in macrophage LpL knockout (MLpLKO) mice. MLpLKO mice were generated using cre-loxP gene targeting. Loss of LpL in macrophages did not alter plasma LpL activity or lipoprotein levels. Incubation of apolipoprotein E (ApoE)-deficient ß-VLDL with peritoneal macrophages from ApoE knockout mice lacking macrophage LpL (MLpLKO/ApoEKO) led to less cholesteryl ester formation than that found with ApoEKO macrophages. MLpLKO/ApoEKO macrophages had reduced intracellular triglyceride levels, with decreased CD36 and carnitine palmitoyltransferase-1 mRNA levels compared with ApoEKO macrophages, when incubated with VLDL. Although both MLpLKO/ApoEKO and ApoEKO mice developed comparable hypercholesterolemia in response to feeding with a Western-type diet for 12 weeks, atherosclerosis was less in MLpLKO/ApoEKO mice. Epididymal fat mass and gene expression levels associated with inflammation did not differ between the two groups. In conclusion, macrophage LpL plays an important role in the development of atherosclerosis but not adiposity.


Asunto(s)
Adiposidad/fisiología , Aterosclerosis/enzimología , Lipoproteína Lipasa/metabolismo , Macrófagos Peritoneales/enzimología , Macrófagos/enzimología , Adiposidad/genética , Animales , Apolipoproteínas E/deficiencia , Apolipoproteínas E/genética , Aterosclerosis/genética , Aterosclerosis/patología , Northern Blotting , Carnitina O-Palmitoiltransferasa/genética , Carnitina O-Palmitoiltransferasa/metabolismo , Lipoproteína Lipasa/genética , Ratones , Ratones Noqueados , Reacción en Cadena en Tiempo Real de la Polimerasa
17.
Arterioscler Thromb Vasc Biol ; 32(8): 1824-31, 2012 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-22701022

RESUMEN

OBJECTIVE: 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) catalyzes the rate-limiting step in cholesterol biosynthesis and has proven to be an effective target of lipid-lowering drugs, statins. The aim of this study was to understand the role of hepatic HMGCR in vivo. METHODS AND RESULTS: To disrupt the HMGCR gene in liver, we generated mice homozygous for a floxed HMGCR allele and heterozygous for a transgene encoding Cre recombinase under the control of the albumin promoter (liver-specific HMGCR knockout mice). Ninety-six percent of male and 71% of female mice died by 6 weeks of age, probably as a result of liver failure or hypoglycemia. At 5 weeks of age, liver-specific HMGCR knockout mice showed severe hepatic steatosis with apoptotic cells, hypercholesterolemia, and hypoglycemia. The hepatic steatosis and death were completely reversed by providing the animals with mevalonate, indicating its essential role in normal liver function. There was a modest decrease in hepatic cholesterol synthesis in liver-specific HMGCR knockout mice. Instead, they showed a robust increase in the fatty acid synthesis, independent of sterol regulatory element binding protein-1c. CONCLUSIONS: Hepatocyte HMGCR is essential for the survival of mice, and its abrogation elicits hepatic steatosis with jaundice and hypoglycemia.


Asunto(s)
Hígado Graso/etiología , Hidroximetilglutaril-CoA-Reductasas NADP-Dependientes/fisiología , Hígado/enzimología , Animales , Femenino , Hidroximetilglutaril-CoA-Reductasas NADP-Dependientes/genética , Masculino , Ratones , Ratones Noqueados , ARN Mensajero/análisis , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/genética
18.
Endocr J ; 60(7): 913-22, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-23574730

RESUMEN

Postprandial hyperglycemia and/or hyperlipidemia can contribute to development of atherosclerosis in patients with type 2 diabetes mellitus (T2DM). The objective of this study was to compare the effects of miglitol and sitagliptin on postprandial glucose and lipid metabolism in patients with T2DM. Thirty-five patients with T2DM were randomized to 2 groups receiving miglitol (150 mg/day) or sitagliptin (50 mg/day). Serum variables related to glucose and lipid metabolism were measured before and after treatment for 10 weeks and at 0, 60, and 120 min using a cookie-loading test (CLT). After 10 weeks of treatment, miglitol (n = 16) and sitagliptin (n = 18) caused a similarly significant decrease in hemoglobin A1c (mean: 7.6% to 7.3% versus 8.0% to 7.6%) and a significant increase in fasting insulin levels, with a greater increase observed in the miglitol group than in the sitagliptin group (p=0.03). In addition, a significant decrease in the change in glucose levels after the CLT was observed in both groups, with a greater decrease observed in the miglitol group than in the sitagliptin group (p=0.02). The miglitol group also showed a greater decrease in the change in insulin levels after the CLT than the sitagliptin group (p<0.01). The lipid and lipoprotein levels did not show any significant differences between the groups after the CLT. Our results suggested that miglitol and sitagliptin treatment resulted in similar glycemic control but that a greater decrease in postprandial glucose and insulin levels was observed with miglitol compared with sitagliptin in patients with T2DM.


Asunto(s)
1-Desoxinojirimicina/análogos & derivados , Glucemia/efectos de los fármacos , Diabetes Mellitus Tipo 2/metabolismo , Hipoglucemiantes/farmacología , Lipoproteínas/metabolismo , Pirazinas/farmacología , Triazoles/farmacología , 1-Desoxinojirimicina/farmacología , 1-Desoxinojirimicina/uso terapéutico , Anciano , Glucemia/metabolismo , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Femenino , Humanos , Hipoglucemiantes/uso terapéutico , Insulina/sangre , Metabolismo de los Lípidos/efectos de los fármacos , Masculino , Persona de Mediana Edad , Periodo Posprandial/efectos de los fármacos , Pirazinas/uso terapéutico , Fosfato de Sitagliptina , Triazoles/uso terapéutico
19.
Nihon Rinsho ; 71(9): 1597-601, 2013 Sep.
Artículo en Japonés | MEDLINE | ID: mdl-24205720

RESUMEN

Hypertriglyceridemia is associated with an increase in very low density lipoprotein (VLDL), chylomicron, intermediate density lipoprotein(IDL). Acquired hyperlipidemia results from various disorders, such as obesity, diabetes mellitus, alcohol overuse, chronic kidney disease, hypothyroidism, and some drugs like thiazide, -blocker, estrogen, etc. It is important to identify secondary causes underlying hypertriglyceridemia before initiating pharmacotherapy, since management of the causative disorders is the first-line therapy. Even if hyperlipidemia is not controlled after treating the underlying disorders, specific lipid -lowering therapy may be required in addition to lifestyle modification. Fibrate, nicotinic acid and eicosapentaenoic acid are utilized to reduce triglyceride levels. Statin and ezetimibe are utilized if non-high density lipoprotein(HDL)-cholesterol is elevated.


Asunto(s)
Hipertrigliceridemia/complicaciones , Lipoproteínas/metabolismo , Triglicéridos/metabolismo , Alcoholismo/complicaciones , Complicaciones de la Diabetes/diagnóstico , Complicaciones de la Diabetes/etiología , Humanos , Hipertrigliceridemia/diagnóstico , Hipertrigliceridemia/tratamiento farmacológico , Hipertrigliceridemia/metabolismo , Enfermedades Renales/complicaciones
20.
J Clin Lipidol ; 17(6): 834-838, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37777472

RESUMEN

Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive disorder caused by mutations in the sterol 27-hydroxylase gene (CYP27A1). Due to the deficiency of 27-hydroxylase, the synthesis of bile acids from cholesterol is impaired and excessive cholestanol accumulates in various tissues, such as the central nervous system, tendons, and lenses. Patients with CTX typically manifest intellectual decline, pyramidal tract symptoms, cerebellar symptoms, tendon xanthomas, juvenile cataracts, neonatal jaundice, chronic diarrhea, osteoporosis, and premature cardiovascular disease. Here, we report the atypical case of a 35-year-old female with CTX having massive xanthomas but without a considerable increase in serum cholestanol levels (3.9 µg/mL). In the differential diagnosis of xanthoma, CTX should not be ruled out even if the serum levels of cholestanol are not high, and genetic testing is necessary to make the appropriate diagnosis.


Asunto(s)
Xantomatosis Cerebrotendinosa , Xantomatosis , Femenino , Recién Nacido , Humanos , Adulto , Xantomatosis Cerebrotendinosa/complicaciones , Xantomatosis Cerebrotendinosa/diagnóstico , Xantomatosis Cerebrotendinosa/genética , Colestanol , Xantomatosis/diagnóstico , Colestanotriol 26-Monooxigenasa/genética , Mutación
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