ヒトC-Reactive Protein (CRP) の脂質代謝における役割

Intermittent fasting from dawn to sunset for 30 consecutive days is associated with anticancer proteomic signature and upregulates key regulatory proteins of glucose and lipid metabolism, circadian clock, DNA repair, cytoskeleton remodeling, immune system and cognitive function in healthy subjects

Obesity-induced insulin resistance leads to abnormalities in glucose, lipid, and amino acid metabolism. Our study examined the differences in insulin-mediated glucose, amino acid, and lipid metabolism between morbidly obese subjects with non-obese controls and the associated changes following sleeve gastrectomy (SG). Non-obese controls and individuals with morbid obesity and scheduled for SG were recruited. Metabolic assessments were performed for all subjects at baseline and at 6months after SG for eight subjects. The hyperinsulinemic-euglycemic clamp technique together with comprehensive metabolomic profiling was used to quantify insulin-mediated glucose, amino acid, and lipid metabolism. Eleven morbidly obese non-diabetic subjects scheduled for SG and nine non-obese controls were recruited. Compared to controls, obese subjects had significantly lower glucose uptake (4.4 ± 0.6 vs. 17.3 ± 2.4mg/kg FFM/min per μU/mL·100) and higher concentration of branched-chain amino acids (BCAAs, 332.5 ± 26.8 vs. 235.3 ± 11.0μM), non-esterified fatty acid (52.9 ± 9.9 vs. 25.6 ± 6.7μM), and lipid-related acylcarnitines (intermediate chain 389.8 ± 32.5 vs. 285.9 ± 20.5; long chain 301.7 ± 22.1 vs. 236.0 ± 13.3nM) during insulin clamp. Body weight significantly reduced at 6months after bariatric surgery (92.5 ± 6.3 vs. 115.2 ± 6.9kg), together with improvements in insulin-mediated glucose uptake, and suppression of BCAAs, non-esterified fatty acids, and lipid-related metabolites. Morbid obesity in Asian individuals was associated with impairment in the regulatory actions of insulin on glucose, amino acid, and lipid metabolism, and these obesity-induced regulatory dysfunctions improved significantly 6months after SG.

This review highlights the recent key advances in our understanding of the role of phospholipid transfer protein in lipid and lipoprotein metabolism. The overexpression of human phospholipid transfer protein in mice is associated with an increase in atherosclerosis. This is consistent with earlier studies using mouse models suggesting that phospholipid transfer protein was pro-atherogenic. The presence of phospholipid transfer protein in macrophages and atherosclerotic lesions suggests that it could be either anti-atherogenic by facilitating lipid efflux or pro-atherogenic by facilitating lipid retention. Phospholipid transfer protein may also be a key player in reverse cholesterol transport, as it interacts with the adenosine triphosphate-binding cassette transporter A1 and facilitates lipid efflux from peripheral cells. Both the release of chymase, a neutral protease, from mast cells and the oxidation of HDL by hypochlorous acid can impair the function of phospholipid transfer protein in reverse cholesterol transport. Studies of phospholipid transfer protein-mediated phospholipid transfer activity in humans support a role for phospholipid transfer protein in hypertriglyceridemia, obesity, diabetes, inflammation and coronary artery disease, and in the modulation of LDL particle density and size. Furthermore, recent evidence suggests that phospholipid transfer protein may play a role in reproductive processes, in lipid and lipoprotein metabolism in the central nervous system, and in neurodegenerative disease. Phospholipid transfer protein is emerging as a multifaceted and multifunctional player in lipid and lipoprotein metabolism, but much additional work will be required to understand the significance of these recent findings for clinical practice.

Study on fatty acid binding protein in lipid metabolism of livestock and poultry

Chicken Sterol Carrier Protein m2/Sterol Carrier Protein x: cDNA Cloning Reveals Evolutionary Conservation of Structure and Regulated Expression

BackgroundDyslipidemia has been associated with hypertension. The present study explored if polymorphisms in genes encoding proteins in lipid metabolism could be used as predictors for the individual response to antihypertensive treatment.MethodsTen single nucleotide polymorphisms (SNP) in genes related to lipid metabolism were analysed by a microarray based minisequencing system in DNA samples from ninety-seven hypertensive subjects randomised to treatment with either 150 mg of the angiotensin II type 1 receptor blocker irbesartan or 50 mg of the β1-adrenergic receptor blocker atenolol for twelve weeks.ResultsThe reduction in blood pressure was similar in both treatment groups. The SNP C711T in the apolipoprotein B gene was associated with the blood pressure response to irbesartan with an average reduction of 19 mmHg in the individuals carrying the C-allele, but not to atenolol. The C16730T polymorphism in the low density lipoprotein receptor gene predicted the change in systolic blood pressure in the atenolol group with an average reduction of 14 mmHg in the individuals carrying the C-allele.ConclusionsPolymorphisms in genes encoding proteins in the lipid metabolism are associated with the response to antihypertensive treatment in a drug specific pattern. These results highlight the potential use of pharmacogenetics as a guide for individualised antihypertensive treatment, and also the role of lipids in blood pressure control.

C-reactive protein (CRP) and cardiovascular disease is a very hot topic at present. Excitement and interest have spilled over dramatically from the scientific literature into the media and popular press leading to much speculative comment. However, rigorously controlled and reproducible studies are now laying the basis for a more realistic consensus. The article in this issue of Arteriosclerosis, Thrombosis, and Vascular Biology from Carmen van den Berg’s laboratory makes a notable contribution to this process. 1 See page 1225 Shortly after its discovery in 1929 as “the acute phase protein,” increased production of CRP was recognized as a characteristic feature of the response to acute myocardial infarction, and until the 1960’s detection of CRP was widely used for routine monitoring of acute rheumatic fever. In 1961 Irving Kushner, in one of the first applications of the then new technique of immunofluorescence, demonstrated the deposition of rabbit CRP in experimental myocardial infarction lesions. The association between CRP and cardiovascular disease thus has a very long history. In 1979 Kushner reported the kinetics of the acute phase CRP response to human acute myocardial infarction, and soon afterward we first investigated critically the behavior of CRP in clinical coronary artery disease and myocardial infarction.2 We observed that persistently elevated circulating CRP concentrations after an infarct were associated with a poor prognosis, although at that time we were focusing mainly on CRP as a sensitive nonspecific marker of all the various complications of coronary occlusion and their treatment. The current phase of interest in CRP and cardiovascular disease started in the early 1990’s with observations of increased CRP concentrations in some patients with “active coronary syndromes” and some individuals with acute myocardial infarction tested very soon after onset of pain, before the acute phase response to infarction could have started. These findings were consistent with the growing recognition at that time of the importance of inflammation in atherogenesis and the inflammatory nature of unstable atherosclerotic lesions. At the same time the large European prospective study (ECAT) of coagulation factors as possible prognostic markers in outpatients with stable and unstable angina unexpectedly revealed that the baseline value of CRP, which had only been included as a control for the acute phase behavior of some clotting proteins, significantly predicted future coronary events.3 The assay used was insufficiently sensitive to detect CRP in many of the samples in the ECAT study, and we therefore developed the first automated high-sensitivity method to re-assay their 3000 samples. Separately we also used this method to study, in collaboration with the Maseri group, carefully characterized patients with severe unstable angina who had not yet experienced any myocardial necrosis. We selected a cut point of 3 mg/L as the upper limit of normal, based on our original 1981 study of 468 healthy volunteer blood donors in whom this was the 90th centile of the CRP distribution. 4 In both the ECAT and the unstable angina studies, increased baseline CRP values were associated with significantly increased risk of future coronary events. 5,6 Subsequently several groups showed independently that baseline CRP measurements are associated with future coronary events in general populations, without known preexisting coronary artery disease. 7–10 In 2000 we reported with Danesh and colleagues the results from the British Regional Heart Study comprising 506 coronary events, 2 as many as in any other such study up to that time, together with a meta-analysis of all previous studies.11 This showed that the relative risk of having a coronary event among individuals with a baseline CRP value in the upper compared with the lower tertile of the CRP distribution was 2.0. In 2004 the Reykjavik Study, comprising 2459 coronary events, showed this relative risk to be 1.45 (95% CI, 1.25 to 168), and meta-analysis of all previously published general populations studies, comprising 7068 patients with coronary events, gave a similar result. 12 The results from this now quite rigorously

HomeCirculationVol. 122, No. 4Response to Letter Regarding Article, “Human C-Reactive Protein Does Not Promote Atherosclerosis in Transgenic Rabbits” Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessLetterPDF/EPUBResponse to Letter Regarding Article, “Human C-Reactive Protein Does Not Promote Atherosclerosis in Transgenic Rabbits” Tomonari Koike, Ying Yu, Jifeng Zhang and Jianglin Fan Yukio Ozaki Shuji Kitajima and Kazutoshi Nishijima Masatoshi Morimoto Teruo Watanabe Sucharit Bhakdi Yujiro Asada Y. Eugene Chen Tomonari KoikeTomonari Koike Department of Molecular Pathology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Yamanashi, Japan Search for more papers by this author , Ying YuYing Yu Department of Molecular Pathology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Yamanashi, Japan Search for more papers by this author , Jifeng ZhangJifeng Zhang Department of Molecular Pathology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Yamanashi, Japan Search for more papers by this author and Jianglin FanJianglin Fan Department of Molecular Pathology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Yamanashi, Japan Search for more papers by this author Yukio OzakiYukio Ozaki Department of Clinical and Laboratory Medicine, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Yamanashi, Japan Search for more papers by this author Shuji KitajimaShuji Kitajima Analytical Research Center for Experimental Sciences, Saga University, Saga, Japan Search for more papers by this author and Kazutoshi NishijimaKazutoshi Nishijima Analytical Research Center for Experimental Sciences, Saga University, Saga, Japan Search for more papers by this author Masatoshi MorimotoMasatoshi Morimoto Department of Rehabilitation, Kumamoto Health Science University, Kumamoto, Japan Search for more papers by this author Teruo WatanabeTeruo Watanabe Fukuoka Wajiro Hospital, Fukuoka, Japan Search for more papers by this author Sucharit BhakdiSucharit Bhakdi Institute of Medical Microbiology and Hygiene, Mainz, Germany Search for more papers by this author Yujiro AsadaYujiro Asada The First Department of Pathology, Faculty of Medicine, Miyazaki University, Miyazaki, Japan Search for more papers by this author Y. Eugene ChenY. Eugene Chen Cardiovascular Center, Department of Internal Medicine, University of Michigan, Ann Arbor, Mich Search for more papers by this author Originally published27 Jul 2010https://doi.org/10.1161/CIRCULATIONAHA.110.951798Circulation. 2010;122:e407We appreciate the comments by Nakajima and Saito on our recent article published in Circulation.1 The major question they raised was why human C-reactive protein (CRP) transgenic rabbits failed to exhibit other metabolic disorders, because emerging data support that CRP levels are elevated in patients with metabolic syndrome.2 It is well documented that elevated plasma CRP levels are associated with many pathological states such as cardiovascular diseases and metabolic syndrome; however, these associations do not necessarily mean that high levels of CRP can cause these diseases. Indeed, population genetics studies have failed to link CRP single-nucleotide polymorphisms to the increased risk of cardiovascular diseases, although CRP single-nucleotide polymorphisms are associated with marked increases in CRP levels.3,4 Also, there is no evidence to date to show that elevation of plasma CRP alone can lead to metabolic syndrome both clinically and experimentally. It is apparent that further experiments with appropriate large-animal models are required to investigate CRP functions in metabolic syndrome. Because metabolic syndrome is composed of several metabolic disorders (eg, hypertension, dyslipidemia, and hyperglycemia), which are mediated by multiple genes and many environmental factors, it is unlikely that overexpression of a single CRP gene in animals can lead to all these abnormalities. In fact, we have recently transgenically expressed human CRP in hypertensive animals and found that in the setting of hypertension, CRP does exert certain detrimental effects on both lipid and glucose metabolism (unpublished data). Taken together, CRP functions in both physiology and pathophysiology remain to be further elucidated with genetically modified large animals, as we reported in the study.1DisclosuresNone. References 1 Koike T, Kitajima S, Yu Y, Nishijima K, Zhang J, Ozaki Y, Morimoto M, Watanabe T, Bhakdi S, Asada Y, Chen YE, Fan J. Human C-reactive protein does not promote atherosclerosis in transgenic rabbits. Circulation. 2009; 120: 2088–2094.LinkGoogle Scholar2 Ridker PM, Buring JE, Cook NR, Rifai N. C-reactive protein, the metabolic syndrome, and risk of incident cardiovascular events: an 8-year follow-up of 14 719 initially healthy American women. Circulation. 2003; 107: 391–397.LinkGoogle Scholar3 Wang Q, Hunt SC, Xu Q, Chen YE, Province MA, Eckfeldt JH, Pankow JS, Song Q. Association study of CRP gene polymorphisms with serum CRP level and cardiovascular risk in the NHLBI Family Heart Study. Am J Physiol Heart Circ Physiol. 2006; 291: H2752–H2757.CrossrefMedlineGoogle Scholar4 Zacho J, Tybjaerg-Hansen A, Jensen JS, Grande P, Sillesen H, Nordestgaard BG. Genetically elevated C-reactive protein and ischemic vascular disease. N Engl J Med. 2008; 359: 1897–1908.CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetails July 27, 2010Vol 122, Issue 4 Advertisement Article InformationMetrics https://doi.org/10.1161/CIRCULATIONAHA.110.951798 Originally publishedJuly 27, 2010 PDF download Advertisement SubjectsAnimal Models of Human DiseaseEpidemiologyMechanismsPathophysiology

See related article, pages 1452–1459 Disruption of the endothelium and its subsequent dysfunction appears to set the stage for atherogenesis.1 The maintenance of vascular homeostasis depends in part on a balance between endothelium-derived relaxing and contracting factors. Alterations in this balance lead to inflammation and the formation of fatty streaks and fibrous plaques. The diminished production or availability of nitric oxide (NO) appears paramount to setting the stage for inflammation and vascular injury. In addition to its vasodilatory effect on the vasculature, endothelium-derived NO promotes endothelial cell growth, survival and migration,2 stimulates angiogenesis and neovascularization in part by endothelial progenitor cell (EPC) recruitment,3 inhibits leukocyte adhesion to the endothelium,4 maintains vascular smooth muscle in a nonproliferative state,5 and limits platelet aggregation and thrombosis.6 Maintenance of an intact and functional endothelium protects against vascular disease while its disruption is detrimental. The study by Schwartz et al,7 in this issue of Circulation Research , adds to our understanding of how C-reactive protein (CRP) works to promote vascular pathology by inhibiting NO synthesis. CRP, long regarded as an acute phase protein and an active participant in the innate immune system, has more recently been linked to the development of cardiovascular disease.8 On the basis of several prospective epidemiologic studies, circulating high sensitivity CRP has emerged as an independent predictor of cardiovascular disease risk in various subgroups of patients, including those without overt cardiovascular disease, patients with stable angina or acute coronary syndromes, and in those with the metabolic syndrome.9–12 In primary prevention, CRP confers additional prognostic value at all levels of Framingham risk score and blood pressure.13,14 However, whether or not CRP plays a direct biological role in the initiation and progression of atherosclerosis is controversial.15,16 …

Effects of Chinese herbal medicine Guanxinkang on lipid metabolism and serum C-reactive protein, amyloid A protein, and fibrinogen in apolipoprotein E-knockout mice with atherosclerosis

In addition to the well-recognized transport function of lipoproteins, a large body of evidence has demonstrated that lipoproteins also play an important role in host defense as part of the innate immune system (for review, see Ref. 1). One of the key defensive functions is the ability of HDL and other lipoproteins to bind endotoxin (lipopolysaccharide, LPS) and other bacterial products and neutralize their toxic effects. In this issue of the Journal of Lipid Research, Wang et al. (2) provide insights into the structural requirements for LPS neutralization by apolipoprotein A-I. The helical structure of apolipoprotein A-I is based on eight similar 22 amino acid and two 11 amino acid tandem repeats, but the areas required for HDL formation and function can now be attributed to specific regions based on studies of specific mutations (3). The central region (amino acids 144–186) activates LCAT and contributes to HDL maturation and stability. The N(44–65) and C(220–241) terminal repeats are necessary to initiate lipid binding, form nascent HDL, and remove cholesterol from macrophages. A larger portion of the C-terminal region (190–243) is critical for phospholipid binding and promoting cholesterol efflux. Naturally occurring mutations of cysteines in apolipoprotein A-I, such as A-IMilano and A-IParis, are associated with protection against atherosclerosis even when HDL cholesterol levels are decreased (4). The paper by Wang et al. (2) addresses what regions of apolipoprotein A-I are required for neutralization of LPS by substituting other amino acids for specific cysteine residues. Serine substitution of one cysteine (228) in the C-terminal domain dramatically reduced the ability of HDL to neutralize LPS, while another C-terminal substitution (cysteine 195), proximal to the last 22 residue repeat, had little effect. Midregion substitutions (cysteines 107, 129, and 173) also had little effect. On the other hand, substitution in the first N-terminal repeat (cysteine 52) and especially the next region (cysteine 74) formed HDL that was more effective at neutralizing LPS and protecting from LPS induced lung injury. Thus, Wang et al. (2) have shown that, as with cholesterol and phospholipid metabolism, specific regions of apolipoprotein A-I are essential for LPS neutralization. Furthermore, the regions involved in LPS neutralization are different than those involved in cholesterol and phospholipid metabolism. For example, these authors have previously shown (5) that substitution for cysteine residues 129 and 195 impaired lipid binding, while substitutions at 173 and 195 impaired the ability of HDL to promote cholesterol efflux. In contrast, a substitution at 107 had an increased capacity to promote cholesterol efflux. As noted above, the substitutions at 52 and 74 enhanced the ability of HDL to neutralize LPS, yet these substitutions had no effect on HDL structure or the ability of HDL to remove cholesterol from macrophages. Consequently, the increase in protection from LPS makes the 52 and 74 substitutions “super” apolipoproteins A-Is for host defense, with little downside in adversely affecting reverse cholesterol transport and increasing the risk of atherosclerosis. It remains to be seen whether similar naturally occurring mutations occur in humans and whether such mutations in apolipoprotein A-I will have a beneficial effect during gram-negative infections. Additionally, studies should examine whether similar modifications of apolipoprotein A-I will also enhance the neutralization of other toxic bacterial products, such as lipoteichoic acid. Infections activate Toll-like receptors stimulating the secretion of cytokines, which have profound effects on lipid and lipoprotein metabolism (for review, see Ref. 1). The changes in lipid and lipoprotein metabolism are part of the acute phase response (APR), a pattern best known for increases in serum proteins (6). Positive APR proteins are those whose circulating levels increase during the APR while negative APR proteins decrease. Two positive APR proteins, C-reactive protein and serum amyloid A, bind to lipoproteins and hence can be considered to be apolipoproteins. The increases in serum proteins during the APR are transcriptionally mediated and usually driven by activation of transcription at NF-kB and NF-IL-6 response elements (6). However, many of the changes in lipid and lipoprotein metabolism are part of the negative

CRP-Marker or Maker of Cardiovascular Disease?Jan Nilsson C -reactive protein (CRP) has emerged as an interesting novel and potentially clinically useful marker for increased cardiovascular risk. 1,2This is an attractive concept because atherosclerosis is a disease characterized by chronic arterial inflammation 3,4 and suggests the possibility that subclinical states of atherosclerosis can be identified by an increase in circulating markers of inflammation before acute events occur.Based on data obtained primarily from in vitro studies it has also been proposed that CRP in itself is actively contributing to disease progression and that it should be considered as true risk factor and consequently as a target for intervention.However, in the present issue of Arteriosclerosis, Thrombosis, and Vascular Biology, two independent reports demonstrate that transgenic overexpression of CRP does not affect the development of atherosclerosis in mice, suggesting that this is not the case.

BackgroundIt has been unclear whether supplemental probiotics therapy improves clinical outcomes in type 2 diabetic patients. This meta-analysis aimed to summarize the effect of probiotics on glucose and lipid metabolism and C-reactive protein (CRP) from 12 randomized controlled trials (RCTs).Material/MethodsAn up-to-date search was performed for all relevant RCTs up to April 2016 from PubMed, Embase, and Cochrane Library. Standardized mean difference (SMD) and weighted mean difference (WMD) were calculated for a fixed-effect and random-effect meta-analysis to assess the impact of supplemental probiotics on fasting plasma glucose (FPG), glycated hemoglobin (HbA1c), fasting insulin, homeostasis model assessment of insulin resistance (HOMA-IR), lipid profile, and CRP level.ResultsA total of 12 studies (684 patients) were entered into the final analysis. The effect of probiotics was significant on reducing HbA1c level (standardized mean difference [SMD], −0.38; confidence interval [CI], −0.62 to −0.14, P=0.002; I2=0%, P=0.72 for heterogeneity), fasting insulin level (SMD, −0.38; CI −0.59 to −0.18, P=0.0003; I2=0%, P=0.81 for heterogeneity), and HOMA-IR (SMD, −0.99; CI −1.52 to −0.47, P=0.0002; I2=86%, P<0.00001 for heterogeneity). Pooled results on effects of probiotics on FPG, CRP, or lipid profile were either non-significant or highly heterogeneous.ConclusionsThis meta-analysis demonstrated that probiotics supplementation was associated with significant improvement in HbA1c and fasting insulin in type 2 diabetes patients. More randomized placebo-controlled trials with large sample sizes are warranted to confirm our conclusions.

Aerobic exercise-induced decrease of chemerin improved glucose and lipid metabolism and fatty liver of diabetes mice through key metabolism enzymes and proteins

Simple SummaryThe liver is a major organ regulating lipid metabolism and a proper liver function is essential to health. Nonalcoholic fatty liver disease (NAFLD) is a condition with abnormal fat accumulation in the liver without heavy alcohol use. NAFLD is becoming one of the most common liver diseases with the increase in obesity in many parts of the world. There is no approved cure for the disease and a better understanding of disease mechanism is needed for effective prevention and treatment. The nuclear envelope, a membranous structure that surrounds the cell nucleus, is connected to the endoplasmic reticulum where the vast majority of cellular lipids are synthesized. Growing evidence indicates that components in the nuclear envelope are involved in cellular lipid metabolism. We review published studies with various cell and animal models, indicating the essential roles of nuclear envelope proteins in lipid metabolism. We also discuss how defects in these proteins affect cellular lipid metabolism and possibly contribute to the pathogenesis of NAFLD.Nonalcoholic fatty liver disease (NAFLD) is a burgeoning public health problem worldwide. Despite its tremendous significance for public health, we lack a comprehensive understanding of the pathogenic mechanisms of NAFLD and its more advanced stage, nonalcoholic steatohepatitis (NASH). Identification of novel pathways or cellular mechanisms that regulate liver lipid metabolism has profound implications for the understanding of the pathology of NAFLD and NASH. The nuclear envelope is topologically connected to the ER, where protein synthesis and lipid synthesis occurs. Emerging evidence points toward that the nuclear lamins and nuclear membrane-associated proteins are involved in lipid metabolism and homeostasis. We review published reports that link these nuclear envelope proteins to lipid metabolism. In particular, we focus on the recent work demonstrating the essential roles for the nuclear envelope-localized torsinA/lamina-associated polypeptide (LAP1) complex in hepatic steatosis, lipid secretion, and NASH development. We also discuss plausible pathogenic mechanisms by which the loss of either protein in hepatocytes leads to hepatic dyslipidemia and NASH development.