RESUMO
BACKGROUND: Numerous epidemiological studies have shown that hypertriglyceridemia is a significant risk factor for cardiovascular diseases (CVD). However, large clinical studies on triglyceride-lowering therapy have yielded inconsistent results. In the current review, we reassess the importance of triglyceride-lowering therapy in preventing CVD based on previous literature and the recently published findings of the PROMINENT trial. METHODS: This narrative review is based on literature and public documents published up to November 2023. RESULTS: Meta-analyses of trials on peroxisome proliferator-activated receptor α agonists and triglyceride-lowering therapy, including the PROMINENT trial, have indicated that triglyceride-lowering therapy can reduce CVD events. Mendelian randomization studies have also indicated that triglyceride is indeed a true risk factor for coronary artery disease, leaving no doubt about its relationship to CVD. Meanwhile, the negative results from the PROMINENT trial were likely due to the insufficient triglyceride-lowering effect, slight increases in low-density lipoprotein cholesterol and apolipoprotein B, and the inclusion of mostly high-intensity statin users as target patients. It is unlikely that adverse events counteracted the effectiveness of pemafibrate on outcomes. Additionally, pemafibrate has shown positive effects on non-alcoholic fatty liver disease and peripheral artery disease. CONCLUSION: Although the PROMINENT trial did not demonstrate the significance of pemafibrate as a triglyceride-lowering therapy in a specific population, it does not necessarily negate the potential benefits of treating hypertriglyceridemia in reducing CVD events. It is necessary to explore appropriate populations that could benefit from this therapy, utilize data from the PROMINENT trial and other databases, and validate findings in real-world settings.
Assuntos
Doenças Cardiovasculares , Hipertrigliceridemia , Humanos , Hipertrigliceridemia/tratamento farmacológico , Hipertrigliceridemia/complicações , Doenças Cardiovasculares/prevenção & controle , Hipolipemiantes/uso terapêutico , Triglicerídeos/sangue , Triglicerídeos/metabolismo , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Benzoxazóis/uso terapêutico , Hepatopatia Gordurosa não Alcoólica/complicações , Doença da Artéria Coronariana/prevenção & controle , LDL-Colesterol , Ensaios Clínicos Controlados Aleatórios como Assunto , ButiratosRESUMO
Severe hypertriglyceridemia is a pathological condition caused by genetic factors alone or in combination with environmental factors, sometimes leading to acute pancreatitis (AP). In this study, exome sequencing and biochemical analyses were performed in 4 patients with hypertriglyceridemia complicated by obesity or diabetes with a history of AP or decreased post-heparin LPL mass. In a patient with a history of AP, SNP rs199953320 resulting in LMF1 nonsense mutation and APOE rs7412 causing apolipoprotein E2 were both found in heterozygous form. Three patients were homozygous for APOA5 rs2075291, and one was heterozygous. ELISA and Western blot analysis of the serum revealed the existence of apolipoprotein A-V in the lipoprotein-free fraction regardless of the presence or absence of rs2075291; furthermore, the molecular weight of apolipoprotein A-V was different depending on the class of lipoprotein or lipoprotein-free fraction. Lipidomics analysis showed increased serum levels of sphingomyelin and many classes of glycerophospholipid; however, when individual patients were compared, the degree of increase in each class of phospholipid among cases did not coincide with the increases seen in total cholesterol and triglycerides. Moreover, phosphatidylcholine, lysophosphatidylinositol, and sphingomyelin levels tended to be higher in patients who experienced AP than those who did not, suggesting that these phospholipids may contribute to the onset of AP. In summary, this study revealed a new disease-causing gene mutation in LMF1, confirmed an association between overlapping of multiple gene mutations and severe hypertriglyceridemia, and suggested that some classes of phospholipid may be involved in the pathogenesis of AP.
Assuntos
Apolipoproteína A-V , Hipertrigliceridemia , Lipase Lipoproteica , Pancreatite , Humanos , Pancreatite/genética , Pancreatite/sangue , Lipase Lipoproteica/genética , Lipase Lipoproteica/sangue , Hipertrigliceridemia/genética , Hipertrigliceridemia/complicações , Hipertrigliceridemia/sangue , Masculino , Feminino , Pessoa de Meia-Idade , Adulto , Apolipoproteína A-V/genética , Apolipoproteínas E/genética , Polimorfismo de Nucleotídeo Único , Sequenciamento do Exoma , Obesidade/complicações , Obesidade/genética , Obesidade/sangue , Doença Aguda , Triglicerídeos/sangue , Proteínas de MembranaRESUMO
BACKGROUND: HDL has been proposed to possess anti-inflammatory properties; however, the detail mechanisms have not been fully elucidated. METHODS: We investigated the roles of Apolipoprotein D (ApoD) in the pathogenesis of inflammation in the mouse model of diet-induced obesity and that of lipopolysaccharide-induced sepsis and the in vitro experiments. Furthermore, we analyzed serum ApoD levels in human subjects. RESULTS: The overexpression of human ApoD decreased the plasma IL-6 and TNF-a levels in both mice models. Lipidomics analyses demonstrated association of ApoD with increase of arachidonic acid, eicosapentaenoic acid, and docosahexaenoic acid, as well as of their metabolites, and of the anti-inflammatory molecule sphingosine 1-phosphate, and decrease of proinflammatory lysophosphatidic acids and lysophosphatidylinositol. ApoD-containing lipoproteins might directly bind eicosapentaenoic acid and docosahexaenoic acid. The modulations of the lysophosphatidic acid and sphingosine 1-phosphate levels resulted from the suppression of autotaxin expression and elevation of apolipoprotein M (ApoM), respectively. Moreover, ApoD negatively regulated osteopontin, a proinflammatory adipokine. The activation of PPARg by ApoD might suppress autotaxin and osteopontin. Serum ApoD levels were negatively correlated with the serum osteopontin and autotaxin levels and, positively with serum ApoM levels. CONCLUSION: ApoD is an anti-inflammatory apolipoprotein, which modulates lipid mediators and osteopontin in an anti-inflammatory direction.
Assuntos
Ácido Eicosapentaenoico , Osteopontina , Humanos , Camundongos , Animais , Apolipoproteínas D/metabolismo , Ácido Eicosapentaenoico/farmacologia , Ácidos Docosa-Hexaenoicos/farmacologia , Anti-Inflamatórios/farmacologia , Lisofosfolipídeos/metabolismo , Eicosanoides , Esfingosina/metabolismoRESUMO
Lysophosphatidylinositol (LPI) is a glycero-lysophospholipid and a natural agonist against GPR55. The roles of the LPI/GPR55 axis in the pathogenesis of inflammation have been controversial. In the present study, we attempted to elucidate the roles of the LPI/GPR55 axis in inflammation, especially the secretion of inflammatory cytokines, IL-6 and TNF-α from macrophages. We treated RAW264.7 cells and mouse peritoneal macrophages (MPMs) with LPI and observed that LPI induced the secretion of IL-6 and TNF-α from these cells, as well as the phosphorylation of p38. These responses were inhibited by treatment with CID16020046 (CID), an antagonist against GPR55, or SB202190, an inhibitor of p38 cascade or knockdown of GPR55 with siRNA. Treatment with CID or ML-193, another antagonist against GPR55, attenuated the elevation of inflammatory cytokines in the plasma or tissue of db/db mice and in a septic mouse model induced using lipopolysaccharide, suggesting contributions to the improvement of insulin resistance and protection against organ injuries by treatment with CID or ML-193, respectively. In human subjects, although the serum LPI levels were not different, the levels of LPI in the lipoprotein fractions were lower and the levels in the lipoprotein-depleted fractions were higher in subjects with diabetes. LPI bound to albumin induced the secretion of IL-6 and TNF-α from RAW264.7 cells to a greater degree than LPI bound to LDL or HDL. These results suggest that LPI, especially the albumin-bound form, induced inflammatory cytokines depending on the GPR55/p38 pathway, which might contribute to the pathogenesis of obesity-induced inflammation and acute inflammation.
Assuntos
Albuminas/metabolismo , Citocinas/metabolismo , Diabetes Mellitus Experimental/imunologia , Diabetes Mellitus Tipo 2/imunologia , Mediadores da Inflamação/metabolismo , Lisofosfolipídeos/farmacologia , Macrófagos/imunologia , Animais , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Humanos , Sistema de Sinalização das MAP Quinases , Macrófagos/metabolismo , Macrófagos/patologia , Camundongos , Camundongos Endogâmicos C57BLRESUMO
Hepatobiliary cholesterol handling, mediated by Niemann-Pick C1-like 1 protein (NPC1L1) and ABCG5/8, is well-known to contribute to the homeostasis of cholesterol. We attempted to elucidate the impact of hepatobiliary cholesterol handling on the homeostasis of sphingolipids and lysophospholipids, especially sphingosine 1-phosphate (S1P). We induced the overexpression of NPC1L1 or ABCG5/8 in the mouse liver. Hepatic NPC1L1 overexpression increased the plasma and hepatic S1P levels, while it decreased the biliary S1P levels, and all of these changes were inhibited by ezetimibe. The ability of HDL to activate Akt in the endothelial cells was augmented by hepatic NPC1L1 overexpression. NPC1L1-mediated S1P transport was confirmed by both in vitro and in vivo studies conducted using C17 S1P, an exogenous S1P analog. Upregulation of apolipoprotein M (apoM) was involved in these modulations, although apoM was not necessary for these modulations. Moreover, the increase in the plasma S1P levels also observed in ABCG5/8-overexpressing mice was dependent on the elevation of the plasma apoM levels. In regard to other sphingolipids and lysophospholipids, ceramides were similarly modulated by NPC1L1 to S1P, while other lipids were differently influenced by NPC1L1 or ABCG5/8 from S1P. Hepatobiliary cholesterol handling might also regulate the functional lipids, such as S1P.
Assuntos
Colesterol/metabolismo , Fígado/metabolismo , Lisofosfolipídeos/metabolismo , Esfingosina/análogos & derivados , Membro 5 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Membro 8 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Animais , Anticolesterolemiantes/farmacologia , Apolipoproteínas M/metabolismo , Ezetimiba/farmacologia , Células Hep G2 , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Fígado/efeitos dos fármacos , Proteínas de Membrana Transportadoras/genética , Proteínas de Membrana Transportadoras/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Esfingosina/metabolismoRESUMO
Serum dehydroepiandrosterone sulfate (DHEA-S) levels reflect the state of adrenocorticotropic hormone (ACTH) secretion. However, it is difficult to use serum DHEA-S to diagnose hypothalamic-pituitary-adrenal (HPA) axis insufficiency due to its non-normal and highly skewed distribution. In this study, we focused on HPA insufficiency caused by hypothalamic and/or pituitary dysfunction and evaluated the usefulness of the standard deviation score of log-transformed DHEA-S (ln DHEA-S SD score), which was calculated from the established age- and sex-specific reference values. We retrospectively reviewed the medical records of 94 patients suspected of having HPA insufficiency, in whom serum DHEA-S measurement and the rapid ACTH stimulation test were performed, and included 65 patients who met our criteria in this study. The ln DHEA-S SD scores were distributed more normally than measured DHEA-S levels and were significantly higher in patients with a peak cortisol level ≥18 µg/dL than in those below this value, suggesting that this score is a legitimate and strong indicator of adrenocortical function. The optimal cut-off value for impaired HPA function was -0.853, with a sensitivity of 70.3% and a specificity of 100%. Among the 37 patients whose peak cortisol levels were below 18 µg/dL, 11 patients with ln DHEA-S scores ≥-0.853 exhibited significantly higher basal ACTH and basal and peak cortisol levels than the 26 patients with scores <-0.853. Thus, this score plays a supportive role in evaluating HPA axis function, particularly in patients with borderline cortisol responses to ACTH.
Assuntos
Insuficiência Adrenal/diagnóstico , Sulfato de Desidroepiandrosterona/sangue , Hipopituitarismo/diagnóstico , Sistema Hipotálamo-Hipofisário/fisiopatologia , Sistema Hipófise-Suprarrenal/fisiopatologia , Insuficiência Adrenal/sangue , Insuficiência Adrenal/fisiopatologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Hipopituitarismo/sangue , Masculino , Pessoa de Meia-Idade , Estudos RetrospectivosRESUMO
Glycero-lysophospholipids, such as lysophosphatidic acids and lysophosphatidylserine, are gathering attention, since specific receptors have been identified. Most of these compounds have been proposed to be bound to albumin, while their associations with lipoproteins have not been fully elucidated. Therefore, in this study, we aimed to investigate the contents of glycero-lysophospholipids (lysophosphatidic acids, lysophosphatidylcholine, lysophosphatidylethanolamine, lysophosphatidylglycerol, lysophosphatidylinositol, and lysophosphatidylserine) on lipoproteins and the modulation of their metabolism by lipoprotein metabolism. We observed that moderate amounts of glycero-lysophospholipids, with the exception of lysophosphatidylserine, were distributed on the LDL and HDL fractions, and glycero-lysophospholipids that had bound to albumin were observed in lipoprotein fractions when they were co-incubated. The overexpression of cholesteryl ester transfer protein decreased the plasma levels of lysophosphatidylcholine, lysophosphatidylethanolamine, lysophosphatidylglycerol, and lysophosphatidylinositol and it increased their contents in apoB-containing lipoproteins, while it decreased their contents in HDL and lipoprotein-depleted fractions in mice. The overexpression of the LDL receptor (LDLr) decreased the plasma levels of lysophosphatidylcholine, lysophosphatidylethanolamine, lysophosphatidylglycerol, and lysophosphatidylinositol and decreased the contents of these compounds in the LDL, HDL, and lipoprotein-depleted fractions, while the knockdown of the LDLr increased them. These results suggest the potential importance of glycero-lysophospholipids in the pleiotropic effects of lipoproteins as well as the importance of lipoprotein metabolism in the regulation of glycero-lysophospholipids.
Assuntos
Dislipidemias/sangue , Lipoproteínas HDL/metabolismo , Lipoproteínas LDL/metabolismo , Lisofosfolipídeos/sangue , Animais , Apolipoproteína B-100/metabolismo , Proteínas de Transferência de Ésteres de Colesterol/genética , Proteínas de Transferência de Ésteres de Colesterol/metabolismo , Vetores Genéticos , Voluntários Saudáveis , Células Hep G2 , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Receptores de LDL/genética , Receptores de LDL/metabolismo , Albumina Sérica/metabolismoRESUMO
BACKGROUND: Mechanisms underlying the frequent association between salt-sensitive hypertension and type 2 diabetes remain obscure. We previously found that protein kinase C (PKC) activation phosphorylates Kelch-like 3 (KLHL3), an E3 ubiquitin ligase component, at serine 433. We investigated whether impaired KLHL3 activity results in increased renal salt reabsorption via NaCl cotransporter (NCC). METHODS: We used the db/db diabetes mouse model to explore KLHL3's role in renal salt handling in type 2 diabetes and evaluated mechanisms of KLHL3 dysregulation in cultured cells. RESULTS: We observed PKC activity in the db/db mouse kidney and phosphorylation of serine 433 in KLHL3 (KLHL3S433-P). This modification prevents binding of with-no-lysine (WNK) kinases; however, total KLHL3 levels were decreased, indicating severely impaired KLHL3 activity. This resulted in WNK accumulation, activating NCC in distal convoluted tubules. Ipragliflozin, a sodium glucose cotransporter 2 (SGLT2) inhibitor, lowered PKC activity in distal convoluted tubule cells and reduced KLHL3S433-P and NCC levels, whereas the thiazolidinedione pioglitazone did not, although the two agents similarly reduced in blood glucose levels. We found that, in human embryonic kidney cells expressing KLHL3 and distal convoluted tubule cells, cellular glucose accumulation increased KLHL3S433-P levels through PKC. Finally, the effect of PKC inhibition in the kidney of db/db mice confirmed PKC's causal role in KLHL3S433-P and NCC induction. CONCLUSIONS: Dysregulation of KLHL3 is involved in the pathophysiology of type 2 diabetes. These data offer a rationale for use of thiazide in individuals with diabetes and provide insights into the mechanism for cardiorenal protective effects of SGLT2 inhibitors.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Glucosídeos/farmacologia , Proteínas dos Microfilamentos/genética , Proteína Quinase C/metabolismo , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Membro 3 da Família 12 de Carreador de Soluto/metabolismo , Tiofenos/farmacologia , Proteína Quinase 1 Deficiente de Lisina WNK/metabolismo , Animais , Proteínas de Transporte/metabolismo , Células Cultivadas , Diabetes Mellitus Experimental/metabolismo , Humanos , Hipertensão/etiologia , Hipertensão/fisiopatologia , Túbulos Renais Distais/citologia , Camundongos , Camundongos Obesos , Proteínas dos Microfilamentos/metabolismo , Fosforilação , Sensibilidade e Especificidade , Transdução de SinaisRESUMO
A 49-year-old woman with membranous nephropathy was referred to our hospital during the tapering of oral prednisolone, because of suspicion of primary adrenal insufficiency based on a plasma ACTH level of 399.1 pg/mL in the Elecsys assay and a serum cortisol level of 3.1 µg/dL. A rapid ACTH stimulation test revealed a suboptimal response, whereas a prolonged ACTH simulation test showed a sufficient increase in her urinary free cortisol. Also, big ACTH was not detected by gel exclusion chromatography. Therefore, we speculated that ACTH levels were falsely elevated due to some interference substances. Pretreatment of her plasma with either polyethylene glycol precipitation or a heterophilic blocking tube substantially reduced her ACTH values. When either the Immulite ACTH II or the TOSOH II ACTH was tried instead of the Elecsys ACTH, her plasma ACTH values turned out to be lower and appropriate for her clinical status. These results indicated that heterophilic antibodies interfered only with the Elecsys ACTH assay presumably by bridging the capture and tracer antibodies. To our knowledge, this is the first case in which the Elecsys ACTH assay yielded falsely elevated results. Regardless of the measurement system used, if there is a discordance between assay results and clinical findings, it should be considered to adopt additional procedures and/or another assay.
Assuntos
Insuficiência Adrenal/diagnóstico , Hormônio Adrenocorticotrópico/sangue , Glomerulonefrite Membranosa/sangue , Insuficiência Adrenal/sangue , Bioensaio , Feminino , Glomerulonefrite Membranosa/tratamento farmacológico , Humanos , Pessoa de Meia-Idade , Prednisolona/uso terapêuticoRESUMO
Apolipoprotein M (apoM) is a carrier and a modulator of sphingosine 1-phosphate (S1P), an important multifunctional bioactive lipid. Since peroxisome proliferator-activated receptor γ (PPARγ) is reportedly associated with the function and metabolism of S1P, we investigated the modulation of apoM/S1P homeostasis by PPARγ. First, we investigated the modulation of apoM and S1P homeostasis by the overexpression or knockdown of PPARγ in HepG2 cells and found that both the overexpression and the knockdown of PPARγ decreased apoM expression and S1P synthesis. When we activated or suppressed the PPARγ more mildly with pioglitazone or GW9662, we found that pioglitazone suppressed apoM expression and S1P synthesis, while GW9662 increased them. Next, we overexpressed PPARγ in mouse liver through adenoviral gene transfer and observed that both the plasma and hepatic apoM levels and the plasma S1P levels decreased, while the hepatic S1P levels increased, in the presence of enhanced sphingosine kinase activity. Treatment with pioglitazone decreased both the plasma and hepatic apoM and S1P levels only in diet-induced obese mice. Moreover, the overexpression of apoM increased, while the knockdown of apoM suppressed PPARγ activities in HepG2 cells. These results suggested that PPARγ regulates the S1P levels by modulating apoM in a bell-shaped manner, with the greatest levels of apoM/S1P observed when PPARγ was mildly expressed and that hepatic apoM/PPARγ axis might maintain the homeostasis of S1P metabolism.
Assuntos
Apolipoproteínas M/metabolismo , Fígado/metabolismo , Lisofosfolipídeos/metabolismo , PPAR gama/metabolismo , Esfingosina/análogos & derivados , Anilidas/farmacologia , Animais , Apolipoproteínas M/genética , Células Hep G2 , Humanos , Lisofosfolipídeos/genética , Camundongos , PPAR gama/antagonistas & inibidores , PPAR gama/genética , Pioglitazona/farmacologia , Esfingosina/genética , Esfingosina/metabolismoRESUMO
The physiological roles of phytosterols in chronic inflammation, which are believed to be involved in the underlying mechanisms for metabolic diseases, have yet to be elucidated. Therefore, in the present study, we aimed to elucidate the physiological roles of phytosterols in both clinical studies and animal experiments. We observed the existence of rather specific negative correlations between the serum sitosterol level and the serum IL-6 and the TNF-α levels in both diabetic subjects (n=46) and non-diabetic subjects (n=178). Multiple regression analyses also revealed that the serum IL-6 and TNF-α levels exhibited strong negative correlations with the serum sitosterol levels. When ABCG5/8 KO mice with markedly elevated plasma sitosterol levels and ABCG5/8 hetero mice were fed a high-fat diet, we observed that the increase in body weight, the fatty liver changes, and the expansion of perigonadal adipose tissues were suppressed in ABCG5/8 KO mice without any modulation of food intake. We also observed that the plasma IL-6 and TNF-α levels, the expressions of TNF-α and PAI-1 in the liver and the expressions of the IL-6, TNF-α, and MCP-1 levels in the adipose tissue were lower in ABCG5/8 KO mice. These results suggest that sitosterol might suppress obesity-related chronic inflammation and might be applicable to the treatment of metabolic diseases.
Assuntos
Interleucina-6/sangue , Obesidade , Sitosteroides , Fator de Necrose Tumoral alfa/sangue , Membro 5 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Membro 5 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Animais , Doença Crônica , Feminino , Humanos , Inflamação/sangue , Inflamação/prevenção & controle , Lipoproteínas/genética , Lipoproteínas/metabolismo , Masculino , Camundongos , Camundongos Knockout , Pessoa de Meia-Idade , Obesidade/sangue , Obesidade/tratamento farmacológico , Sitosteroides/administração & dosagem , Sitosteroides/farmacocinéticaRESUMO
OBJECTIVE: Sphingosine-1-phosphate (S1P) is a vasoprotective lipid mediator. About two thirds of plasma S1P rides on high-density lipoprotein (HDL), and several pleiotropic properties of HDL have been ascribed to S1P. In human subjects, CETP (cholesteryl ester transfer protein) greatly influences HDL quantities. In this study, we attempted to elucidate the roles of CETP in the metabolism of S1P. APPROACH AND RESULTS: We overexpressed CETP in mice that lacked CETP and found that CETP overexpression decreased the HDL level but failed to modulate the levels of S1P and apolipoprotein M (apoM), a carrier of S1P, in the total plasma. We observed, however, that the distribution of S1P and apoM shifted from HDL to apoB-containing lipoproteins. When we administered C17S1P bound to apoM-containing lipoprotein, C17S1P and apoM were rapidly transferred to apoB-containing lipoproteins in CETP-overexpressing mice. When HDL containing C17S1P was mixed with low-density lipoprotein ex vivo, C17S1P shifted to the low-density lipoprotein fraction independent of the presence of CETP. Concordant with these results, apoM was distributed mainly to the same fraction as apo AI in a CETP-deficient subject, although apoM was also detected in apo AI-poor fractions in a corresponding hypercholesterolemia subject. About the bioactivities of S1P carried on each lipoprotein, S1P riding on apoB-containing lipoproteins induced the phosphorylation of Akt (AKT8 virus oncogene cellular homolog) and eNOS (endothelial nitric oxide synthase) in human umbilical vein endothelial cells, and CETP overexpression increased insulin secretion and sensitivity, which was inhibited by an S1P receptor 1 or 3 antagonist. CONCLUSIONS: CETP modulates the distribution of S1P among lipoproteins, which affects the bioactivities of S1P.
Assuntos
Proteínas de Transferência de Ésteres de Colesterol/deficiência , Erros Inatos do Metabolismo Lipídico/sangue , Lipoproteínas/sangue , Lisofosfolipídeos/sangue , Esfingosina/análogos & derivados , Animais , Apolipoproteína B-100/sangue , Apolipoproteínas/sangue , Apolipoproteínas B/sangue , Apolipoproteínas M , Bile/metabolismo , Proteínas de Transferência de Ésteres de Colesterol/sangue , Proteínas de Transferência de Ésteres de Colesterol/genética , Proteínas de Transferência de Ésteres de Colesterol/metabolismo , Genótipo , Células Hep G2 , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Erros Inatos do Metabolismo Lipídico/genética , Lipocalinas/sangue , Lipoproteínas HDL/sangue , Fígado/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Fenótipo , Esfingosina/sangue , Fatores de Tempo , TransfecçãoRESUMO
Sphingosine 1-phosphate (S1P) is a vasoactive lipid mediator that is speculated to be involved in various aspects of atherosclerosis. About 70% of circulating plasma S1P is carried on HDL, and several pleiotropic properties of HDL have been ascribed to S1P. In the previous study with human subjects, however, LDL cholesterol or apoB, but not HDL cholesterol or apoA-I, had a significant positive correlation with the plasma S1P level, suggesting that the metabolic pathway for LDL might have some roles in the metabolism of S1P. In this study, we analyzed the association between LDL receptor, an important protein in the clearance of LDL, and circulating S1P. We observed that in LDL receptor-overexpressing mice, the plasma S1P levels as well as apolipoprotein M (apoM), a carrier of S1P, were decreased and that exogenously administered C17S1P bound to apoM-containing lipoproteins was cleared more rapidly. Unlike the situation in wild-type mice, LDL receptor overexpression in apoE-deficient mice did not reduce the plasma S1P or apoM levels, suggesting that apoE might be a ligand for the LDL receptor during the clearance of these factors. The present findings clarify the novel roles of the LDL receptor and apoE in the clearance of S1P, a multifunctional bioactive phospholipid.
Assuntos
Apolipoproteínas E/metabolismo , Apolipoproteínas/metabolismo , Regulação da Expressão Gênica , Lisofosfolipídeos/sangue , Receptores de LDL/metabolismo , Esfingosina/análogos & derivados , Animais , Apolipoproteínas M , Colesterol/sangue , HDL-Colesterol/metabolismo , DNA Complementar/metabolismo , Ensaio de Imunoadsorção Enzimática , Células Hep G2 , Humanos , Ligantes , Fígado/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Análise de Regressão , Esfingosina/sangueRESUMO
Previous reports including genome-wide association studies (GWASs) have described associations of serum lipids with genomic variations. In the present study, we examined the association of â¼2.5 million single-nucleotide polymorphisms (SNPs) from 3041 Japanese healthy volunteers obtained from the Japan Pharmacogenomics Data Science Consortium (JPDSC) database with serum lipids. We confirmed the previously reported associations of 14 SNPs in 5 regions for low-density lipoprotein (LDL) cholesterol, 23 SNPs in 12 regions for high-density lipoprotein (HDL) cholesterol, 16 SNPs in 6 regions for triglyceride and 5 SNPs in 1 region for phospholipid. Furthermore, we identified 16 possible novel candidate genes associated with LDL cholesterol, HDL cholesterol or triglycerides, where SNPs had P-values of <1 × 10(-5). Further replication analyses of these genes with Korean data revealed significant associations of SNPs located within the PCSK7 gene and triglyceride (Pmeta=7.98 × 10(-9) and 1.91 × 10(-8) for rs508487 and rs236911, respectively). These associations remained significant even by the conditional analysis adjusting for three neighboring variations associated with triglyceride. Our present data suggest that PCSK7 as well as PCSK9 may be associated with lipids, especially triglyceride, and may serve as a candidate for a new drug target to treat lipid abnormality syndromes.
Assuntos
Estudo de Associação Genômica Ampla , Lipídeos/sangue , Polimorfismo de Nucleotídeo Único , Subtilisinas/genética , Triglicerídeos/sangue , Feminino , Genótipo , Voluntários Saudáveis , Humanos , Masculino , Fenótipo , Vigilância da PopulaçãoRESUMO
OBJECTIVE: Lysophosphatidic acids (LPA) have important roles in the field of vascular biology and are derived mainly from lysophosphatidylcholine via autotaxin. However, in our previous study, only the plasma LPA levels, and not the serum autotaxin levels, increased in patients with acute coronary syndrome (ACS). The aim of this study was to elucidate the pathway by which LPA is increased in patients with ACS. APPROACH AND RESULTS: We measured the plasma lysophospholipids species in 141 consecutive patients undergoing coronary angiography (ACS, n=38; stable angina pectoris, n=71; angiographically normal coronary arteries, n=32) using a liquid chromatography-tandem mass spectrometry analysis. Among the ACS subjects, notable increases in the 22:6 LPA, 18:2 LPA, and 20:4 LPA levels were observed. The in vitro experiments revealed that serum incubation mainly increased the 18:2 LPA level, whereas platelet activation increased the 20:4 LPA level. Minor lysophospholipids other than LPA were also elevated in ACS subjects and were well correlated with the corresponding LPA species, including 22:6 LPA. A multiple regression analysis also revealed that lysophosphatidylinositol, lysophosphatidylcholine, lysophosphatidylethanolamine, and lysophosphatidylglycerol were independent explanatory variables for several LPA species. CONCLUSIONS: Specific LPA species, especially long-chain unsaturated LPA, were elevated in ACS patients, along with the corresponding minor lysophospholipids. The elevation of these LPA species might be mainly caused by presently unidentified LPA-producing pathway(s). Minor lysophospholipids might be involved in the generation of LPA, especially 22:6 LPA, and in the pathogenesis of ACS.
Assuntos
Síndrome Coronariana Aguda/sangue , Lisofosfolipídeos/sangue , Síndrome Coronariana Aguda/diagnóstico , Biomarcadores/sangue , Plaquetas/metabolismo , Cromatografia Líquida , Angiografia Coronária , Feminino , Humanos , Lipoproteínas LDL/sangue , Masculino , Diester Fosfórico Hidrolases/sangue , Ativação Plaquetária , Valor Preditivo dos Testes , Espectrometria de Massas em Tandem , Regulação para CimaRESUMO
BACKGROUNDS: High-density lipoprotein (HDL) has been proposed to enhance ß-cell functions. Clinical studies have suggested that apolipoprotein M (apoM), which rides mainly on HDL, is involved in diabetes; however, the underlying mechanism has not yet been elucidated. Recently, apoM was shown to be a carrier for sphingosine 1-phosphate (S1P), a bioactive lipid mediator. In the present study, we investigated the modulation of insulin secretion by apoM through the action of S1P. METHODS AND RESULTS: We overexpressed apoM in the livers of C57BL6 mice using adenovirus gene transfer and found that the blood glucose levels under ad libitum feeding conditions were lower in the apoM-overexpressing mice. While an insulin tolerance test revealed that insulin sensitivity was not significantly affected, a glucose tolerance test revealed that apoM-overexpressing mice had a better glucose tolerance because of enhanced insulin secretion, a phenomenon that was reversed by treatment with VPC 23019, an antagonist against S1P1 and S1P3 receptor. In vitro experiments with MIN6 cells also revealed that apoM-containing lipoproteins enhanced insulin secretion, which was again inhibited by VPC 23019. ApoM retarded the degradation of S1P, and an increase in Pdx1 expression, the attenuation of endoreticulum stress, and the phosphorylation of Akt, AmpK, and Erk were observed as possible underlying mechanisms for the effect of S1P, maintained at a high concentration by apoM, on the increase in insulin secretion. CONCLUSIONS: ApoM augmented insulin secretion by maintaining the S1P concentration under both in vivo and in vitro conditions.
Assuntos
Apolipoproteínas/genética , Células Secretoras de Insulina/metabolismo , Insulina/metabolismo , Lisofosfolipídeos/metabolismo , Esfingosina/análogos & derivados , Proteínas Quinases Ativadas por AMP/genética , Proteínas Quinases Ativadas por AMP/metabolismo , Adenoviridae/genética , Animais , Apolipoproteínas/metabolismo , Apolipoproteínas M , Transporte Biológico , Glicemia/metabolismo , Linhagem Celular , MAP Quinases Reguladas por Sinal Extracelular/genética , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Regulação da Expressão Gênica , Vetores Genéticos , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Insulina/biossíntese , Secreção de Insulina , Células Secretoras de Insulina/citologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Fosforilação , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores de Lisoesfingolipídeo/genética , Receptores de Lisoesfingolipídeo/metabolismo , Transdução de Sinais , Esfingosina/metabolismo , Receptores de Esfingosina-1-Fosfato , Transativadores/genética , Transativadores/metabolismoRESUMO
Endogenous hypertriglyceridemia, which includes familial hypertriglyceridemia and idiopathic hypertriglyceridemia, is characterized by the increased level of VLDL-triglycerides in the blood. Increased production of VLDL from the liver and the decreased catabolism of VLDL-TG in the vessel, which are also the main metabolic features of insulin resistance, have been proposed to be the causes of endogenous hypertriglyceridemia. Genetic factors responsible for endogenous hypertriglyceridemia have been elucidated in several studies, however, these factors have so far not been clearly identified yet; thus the causes of endogenous hypertriglyceridemia would be polygenic. Recent advances in the genetic analytical methods like genome-wide association study would hopefully unveil the whole pictures of endogenous hypertriglyceridemia.
Assuntos
Hipertrigliceridemia/etiologia , Lipoproteínas VLDL/metabolismo , Triglicerídeos/metabolismo , Estudo de Associação Genômica Ampla/métodos , Humanos , Hipertrigliceridemia/metabolismo , Hipertrigliceridemia/terapia , Insulina/metabolismo , Resistência à Insulina/genética , Resistência à Insulina/imunologia , Fatores de RiscoRESUMO
Diabetic nephropathy remains a common cause of end-stage renal failure and its associated mortality around the world. Sphingosine 1-phosphate (S1P) is a multifunctional lipid mediator and binds to HDL via apolipoprotein M (ApoM). Since HDL has been reported to be epidemiologically associated with kidney disease, we attempted to investigate the involvement of the ApoM/S1P axis in the pathogenesis/progression of diabetic nephropathy. In type 2 diabetic patients, the serum ApoM levels were inversely correlated with the clinical stage of diabetic nephropathy. The decline in the eGFR over a 5-year observation period proceeded more rapidly in subjects with lower serum ApoM levels. In a mouse model of streptozotocin-induced diabetes, deletion of ApoM deteriorated the phenotypes of diabetic nephropathy: the urinary albumin and plasma creatinine levels increased, the kidneys enlarged, and renal fibrosis and thickening of the basement membrane progressed. On the other hand, overexpression of ApoM ameliorated these phenotypes. These protective effects of ApoM were partially inhibited by treatment with VPC23019, an antagonist of S1P1 and S1P3, but not by treatment with JTE013, an antagonist of S1P2. ApoM/S1P axis attenuated activation of the Smad3 pathway, while augmented eNOS phosphorylation through the S1P1 pathway. Moreover, ApoM/S1P increased the SIRT1 protein levels and enhanced mitochondrial functions by increasing the S1P content of the cell membrane, which might cause selective activation of S1P1. ApoM might be a useful biomarker for predicting the progression of diabetic nephropathy, and the ApoM/S1P-S1P1 axis might serve as a novel therapeutic target for preventing the development/progression of diabetic nephropathy.
Assuntos
Diabetes Mellitus , Nefropatias Diabéticas , Camundongos , Animais , Apolipoproteínas M/genética , Apolipoproteínas M/metabolismo , Apolipoproteínas/genética , Apolipoproteínas/metabolismo , Apolipoproteínas/farmacologia , Nefropatias Diabéticas/prevenção & controle , EsfingosinaRESUMO
Objective: This study evaluated the changes in the status of glycemic control and lipid management in patients with diabetes under COVID-19 containment restrictions, in order to better understand the impacts of events causing lifestyle restrictions. Patient characteristics with worsened glycemic control were also assessed. Methods: We conducted a retrospective and observational cohort study using the electronic health records of 5,169 patients with diabetes seeking medical care in two healthcare centers. Laboratory test results including glycemic and lipid goal attainment rates were compared between pre-COVID-19 (January to December 2019) and the first wave of COVID-19 (February to June 2020). Multiple regression models were used to evaluate the association between glycated hemoglobin (HbA1c) at baseline and during the first wave with covariates such as concomitant medications and comorbidities. Results: The HbA1c goal achievement rate improved significantly from 39.0% to 43.1% (p < 0.0001) overall, and more patients reached their glycemic target during COVID-19 restrictions. No significant changes were observed in lipid control. An indexed change in HbA1c level showed that glycemic control improved in 2,230 patients and worsened in 1,619 patients. Administration of insulin, GLP-1, and sulfonylureas were each identified as factors correlated with elevated HbA1c, during the first wave of COVID-19. Conclusion: Although the glycemic control in patients with diabetes improved overall under COVID-19 restrictions, those on insulin, GLP-1, or sulfonylureas worsened. These findings suggest the need to better understand what drives differences in glycemic control to better support people with diabetes for future epidemiological outbreaks. Supplementary Information: The online version contains supplementary material available at 10.1007/s40200-023-01302-5.
RESUMO
Niemann-Pick C1-like 1 protein (NPC1L1), a transporter crucial in intestinal cholesterol absorption, is expressed in human liver but not in murine liver. To elucidate the role of hepatic NPC1L1 on lipid metabolism, we overexpressed NPC1L1 in murine liver utilizing adenovirus-mediated gene transfer. C57BL/6 mice, fed on normal chow with or without ezetimibe, were injected with NPC1L1 adenovirus (L1-mice) or control virus (Null-mice), and lipid analyses were performed five days after the injection. The plasma cholesterol levels increased in L1-mice, and FPLC analyses revealed increased cholesterol contents in large HDL lipoprotein fractions. These fractions, which showed α-mobility on agarose electrophoresis, were rich in apoE and free cholesterol. These lipoprotein changes were partially inhibited by ezetimibe treatment and were not observed in apoE-deficient mice. In addition, plasma and VLDL triglyceride (TG) levels decreased in L1-mice. The expression of microsomal triglyceride transfer protein (MTP) was markedly decreased in L1-mice, accompanied by the reduced protein levels of forkhead box protein O1 (FoxO1). These changes were not observed in mice with increased hepatic de novo cholesterol synthesis. These data demonstrate that cholesterol absorbed through NPC1L1 plays a distinct role in cellular and plasma lipid metabolism, such as the appearance of apoE-rich lipoproteins and the diminished VLDL-TG secretion.