Identification and characterisation of a rare MTTP variant underlying hereditary non-alcoholic fatty liver disease.
Identification and characterisation of a rare MTTP variant underlying hereditary non-alcoholic fatty liver disease.
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DOI：
10.1016/j.jhepr.2023.100764
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发表时间：
2023-08
期刊：
影响因子：
8.3
通讯作者：
Aithal, Guruprasad P.
中科院分区：
文献类型：
--
作者：
Grove, Jane I.;Lo, Peggy C. K.;Shrine, Nick;Barwell, Julian;V. Wain, Louise;Tobin, Martin D.;Salter, Andrew M.;Borkar, Aditi N.;Cuevas-Ocana, Sara;Bennett, Neil;John, Catherine;Ntalla, Ioanna;Jones, Gabriela E.;Neal, Christopher P.;Thomas, Mervyn G.;Kuht, Helen;Gupta, Pankaj;Vemala, Vishwaraj M.;Grant, Allister;Adewoye, Adeolu B.;Shenoy, Kotacherry T.;Balakumaran, Leena K.;Hollox, Edward J.;Hannan, Nicholas R. F.;Aithal, Guruprasad P.
关键词：
非酒精性脂肪性肝病(NAFLD)是一种复杂的特征，全球估计患病率为25%。我们的目标是确定一个四代NAFLD家族的遗传变异，该家族的进展性NAFLD会导致肝硬变、失代偿和肝细胞癌的发展，但没有常见的危险因素，如肥胖和2型糖尿病。外显子组测序和基因组比较被用来确定可能的因果变异。我们广泛地描述了家族成员的临床表型和餐后代谢反应，并与健康的非携带者和野生型NAFLD患者进行了比较。变异表达的肝细胞样细胞(HLCs)来源于人类诱导的多能干细胞，来源于纯合子供体皮肤成纤维细胞，并使用CRISPR-Cas9恢复为野生型。通过成像、靶向RNA分析和分子表达阵列对表型进行评估。我们在MTTP中发现了一种罕见的原因变异c.1691T>；Cp.I564T(Rs745447480)，它编码微粒体甘油三酯转移蛋白(MTP)，与进行性NAFLD相关，与代谢综合征无关，没有血脂蛋白血症的特征。来自纯合子供者的HLCs的MTP活性和脂蛋白ApoB分泌量显著低于野生型细胞，而MTP的mRNA和蛋白水平与野生型细胞相似。甘油三酯在HLCs中的胞浆蓄积引发内质网应激、促炎介质的分泌和活性氧的产生。我们已经确定并表征了MTTP中一种罕见的原因变异，MTTP p.I564T的纯合与进行性NAFLD相关，而没有任何其他非血脂蛋白血症的表现。我们的发现为推动进行性NAFLD的机制提供了洞察力。在一个没有典型疾病危险因素的四代家庭中，MTTP基因的一种罕见的遗传变异被确定为导致严重的非酒精性脂肪性肝病的原因。含有这种变异基因的细胞系培养的特点是了解这种基因变异是如何导致肝细胞缺陷的，这会导致脂肪积累和促进疾病的过程。这现在是研究疾病途径和发现治疗常见类型脂肪肝的新方法的有用模型。一种罕见的MTTP变异p.I564T会导致进行性脂肪性肝病和肝硬变。表达MTP 564T的肝细胞样细胞降低了肝脂蛋白的分泌能力。活性氧、核因子-κB途径和细胞外基质重塑驱动脂毒性。
Non-alcoholic fatty liver disease (NAFLD) is a complex trait with an estimated prevalence of 25% globally. We aimed to identify the genetic variant underlying a four-generation family with progressive NAFLD leading to cirrhosis, decompensation, and development of hepatocellular carcinoma in the absence of common risk factors such as obesity and type 2 diabetes. Exome sequencing and genome comparisons were used to identify the likely causal variant. We extensively characterised the clinical phenotype and post-prandial metabolic responses of family members with the identified novel variant in comparison with healthy non-carriers and wild-type patients with NAFLD. Variant-expressing hepatocyte-like cells (HLCs) were derived from human-induced pluripotent stem cells generated from homozygous donor skin fibroblasts and restored to wild-type using CRISPR-Cas9. The phenotype was assessed using imaging, targeted RNA analysis, and molecular expression arrays. We identified a rare causal variant c.1691T>C p.I564T (rs745447480) in MTTP, encoding microsomal triglyceride transfer protein (MTP), associated with progressive NAFLD, unrelated to metabolic syndrome and without characteristic features of abetalipoproteinaemia. HLCs derived from a homozygote donor had significantly lower MTP activity and lower lipoprotein ApoB secretion than wild-type cells, while having similar levels of MTP mRNA and protein. Cytoplasmic triglyceride accumulation in HLCs triggered endoplasmic reticulum stress, secretion of pro-inflammatory mediators, and production of reactive oxygen species. We have identified and characterised a rare causal variant in MTTP, and homozygosity for MTTP p.I564T is associated with progressive NAFLD without any other manifestations of abetalipoproteinaemia. Our findings provide insights into mechanisms driving progressive NAFLD. A rare genetic variant in the gene MTTP has been identified as responsible for the development of severe non-alcoholic fatty liver disease in a four-generation family with no typical disease risk factors. A cell line culture created harbouring this variant gene was characterised to understand how this genetic variation leads to a defect in liver cells, which results in accumulation of fat and processes that promote disease. This is now a useful model for studying the disease pathways and to discover new ways to treat common types of fatty liver disease. A rare MTTP variant, p.I564T, leads to progressive fatty liver disease and cirrhosis. Hepatocyte-like cells expressing MTP 564T have reduced liver lipoprotein secretion capability. Reactive oxygen species, NF-κB pathway, and extracellular matrix remodelling drive lipotoxicity.
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