スフィンゴシン1-リン酸の2型受容体を介する新規肥満・NASH治療の基礎的検討

多様な機能をもつリゾリン脂質メディエーターのスフィンゴシン1-リン酸（S1P）がその2型受容体（S1P2）を介して肥満に及ぼす影響を調べた．食事誘導性肥満モデルにおいて，S1P2欠損マウスでは精巣上体白色脂肪組織重量が増加し，肝脂肪が減少する傾向を示した．さらにS1P2欠損マウスでは，低温環境下での体温維持能力が低下しており，基礎的なエネルギー消費能力が低下していることが示唆された.Sphingosine 1-phosphate (S1P) is bioactive lysophospholipid mediator interacting with five receptors. Here, we investigated the roles of S1P receptor 2 (S1P2) in obesity. S1P2-deficient mice (S1P2 KO) fed high-fat diet showed increased epididymal white adipose tissue weight and decreased liver fat. Moreover, acute cold exposure evoked hypothermia in S1P2 KO mice than in WT mice, showing thermogenic activity is decreased in S1P2 KO mice.研究課題/領域番号:17K16144, 研究期間(年度):2017-04-01 - 2019-03-31出典：研究課題「スフィンゴシン1-リン酸の2型受容体を介する新規肥満・NASH治療の基礎的検討」課題番号17K16144（KAKEN：科学研究費助成事業データベース（国立情報学研究所）） （https://kaken.nii.ac.jp/report/KAKENHI-PROJECT-17K16144/17K16144seika/）を加工して作

Gadoxetic acid-enhanced magnetic resonance imaging to predict paritaprevir-induced hyperbilirubinemia during treatment of hepatitis C.

Paritaprevir inhibits organic anion-transporting polypeptide (OATP)1B1 and OATP1B3, which transport bilirubin. Hyperbilirubinemia is an adverse event reported during hepatitis C treatment. Gadoxetic acid is also transported by OATP1B1/1B3. We evaluated whether the enhancement effect in gadoxetic acid-enhanced magnetic resonance (MR) imaging could predict the plasma concentration of paritaprevir and might anticipate the development of hyperbilirubinemia.This prospective study evaluated 27 patients with hepatitis C who underwent gadoxetic acid-enhanced MR imaging prior to treatment with ombitasvir, paritaprevir, and ritonavir. The contrast enhancement index (CEI), a measure of liver enhancement during the hepatobiliary phase, was assessed. Plasma trough concentrations, and concentrations at 2, 4, and 6 h after dosing were determined 7 d after the start of treatment.Seven patients (26%) developed hyperbilirubinemia (≥ 1.6 mg/dl). Paritaprevir trough concentration (Ctrough) was significantly higher in patients with hyperbilirubinemia than in those without (p = 0.022). We found an inverse relationship between CEI and Ctrough (r = 0.612, p = 0.001), while there was not a significantly weak inverse relationship between AUC0-6 h and CEI (r = -0.338, p = 0.085). The partial correlation coefficient between CEI and Ctrough was -0.425 (p = 0.034), while excluding the effects of albumin and the FIB-4 index. Receiver operating characteristic (ROC) curve analysis showed that the CEI was relatively accurate in predicting hyperbilirubinemia, with area under the ROC of 0.882. Multivariate analysis showed that the CEI < 1.61 was the only independent predictor related to the development of hyperbilirubinemia, with an odds ratio of 9.08 (95% confidence interval 1.05-78.86, p = 0.046).Hepatic enhancement with gadoxetic acid was independently related to paritaprevir concentration and was an independent pretreatment factor in predicting hyperbilirubinemia. Gadoxetic acid-enhanced MR imaging can therefore be useful in determining the risk of paritaprevir-induced hyperbilirubinemia

Elevated Serum Levels of Arachidonoyl-lysophosphatidic Acid and Sphingosine 1-Phosphate in Systemic Sclerosis

<p>Systemic sclerosis (SSc) is an often fatal disease characterized by autoimmunity and inflammation, leading to widespread vasculopathy and fibrosis. Lysophosphatidic acid (LPA), a bioactive phospholipid in serum, is generated from lysophospholipids secreted from activated platelets in part by the action of lysophospholipase D (lysoPLD). Sphingosine 1-phosphate (S1P), a member of the bioactive lysophospholipid family, is also released from activated platelets. Because activated platelets are a hallmark of SSc, we wanted to determine whether subjects with SSc have altered serum lysophospholipid levels or lysoPLD activity. Lysophospholipid levels were measured using mass spectrometric analysis. LysoPLD activity was determined by quantifying choline released from exogenous lysophosphatidylcholine (LPC). The major results were that serum levels of arachidonoyl (20:4)-LPA and S1P were significantly higher in SSc subjects versus controls. Furthermore, serum LPA:LPC ratios of two different polyunsaturated phospholipid molecular species, and also the ratio of all species combined, were significantly higher in SSc subjects versus controls. No significant differences were found between other lysophospholipid levels or lysoPLD activities. Elevated 20:4 LPA, S1P levels and polyunsaturated LPA:LPC ratios may be markers for and/or play a significant role in the etiology of SSc and may be future pharmacological targets for SSc treatment.</p

Correlation coefficients and partial correlation coefficients between variables.

<p>Correlation coefficients and partial correlation coefficients between variables.</p

ROC curve analysis of each baseline parameter and prediction of hyperbilirubinemia.

<p>ROC curve analysis of each baseline parameter and prediction of hyperbilirubinemia.</p