Scientific Business Abstracts of the 113th Annual Meeting of the Association of Physicians of Great Britain and Ireland.
Scientific Business Abstracts of the 113th Annual Meeting of the Association of Physicians of Great Britain and Ireland.
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大不列颠及爱尔兰医师协会第 113 届年会科学商业摘要。
DOI：
10.1093/qjmed/hcz175
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发表时间：
2019
期刊：
影响因子：
--
通讯作者：
Cacciottolo TM
中科院分区：
文献类型：
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作者：
Cacciottolo TM
目的近年来，肥胖及其相关的心脏代谢并发症的患病率急剧上升。在肥胖遗传学研究（n= 7000）中，我们确定了15种与年轻时肥胖和肝硬化相关的SRC-1罕见功能丧失变体。我们假设SRC-1在人外周脂质代谢中起着至关重要的作用。MethodsTo测试SRC-1对脂质代谢的影响，我们敲低SRC-1在hepG 2细胞中，使用qPCR定量表达关键酶，并使用Seahorse Bioscience通量分析仪测量外源性脂肪酸氧化。在人类变异携带者中，我们进行开放式脂肪组织活检，并使用天狼星红染色评估纤维化的组织学。肝纤维化定量使用磁共振elastography.ResultsSRC-1敲低引起75%的CYP 7A 1和80%的CPT 1a，胆固醇catalysts和脂肪酸氧化的限速酶的表达减少，分别减少;和外源性棕榈酸氧化显着减少。在人类中，我们发现显着的胰岛素抵抗（平均HOMA-IR= 3.2），严重的纤维化，40%的脂肪组织活检和先进的肝纤维化或肝硬化的cases.ConclusionsSRC-1变异与脂肪组织纤维化的高风险。肝细胞无法处理过量脂质可能导致脂毒性和加速肝纤维化。
AimThe prevalence of obesity and associated cardiometabolic complications has risen sharply in recent years. Within the Genetics of Obesity Study (n= 7000) we identified 15 rare loss of function variants in SRC-1 associated with obesity and liver cirrhosis at a young age. We hypothesized that SRC-1 plays a crucial role in human peripheral lipid metabolism.MethodsTo test the effect of SRC-1 on lipid metabolism, we knocked down SRC-1 in hepG2 cells, quantified expression of key enzymes using qPCR and measured exogenous fatty acid oxidation using the Seahorse Bioscience flux analyser. In human variant carriers, we performed open adipose tissue biopsies and assessed histology for fibrosis using Sirius red stain. Hepatic fibrosis was quantified using magnetic resonance elastography.ResultsSRC-1 knock-down caused 75% reduction in expression of CYP7A1 and 80% reduction in expression of CPT1a, the rate limiting enzymes for cholesterol catabolism and fatty acid oxidation, respectively; and significant reduction in exogenous palmitate oxidation. In humans, we found significant insulin resistance (mean HOMA-IR= 3.2), severe fibrosis in 40% adipose tissue biopsies and advanced liver fibrosis or cirrhosis in 27% of cases.ConclusionsSRC-1 variants are associated with a high risk of adipose tissue fibrosis. The inability of hepatocytes to handle excess lipid may lead to lipotoxicity and accelerated liver fibrosis.