Lipase Maturation Factor 1 in Hypertriglyceridemia

原发性高甘油三酯血症(HTG)是一种常见的以血浆甘油三酯异常升高为特征的血脂异常的临床表现。HTG与心血管疾病的风险增加有关，在其严重的表现中，还与急性胰腺炎、发作性黄瘤、视网膜脂肪血症和肝脾肿大有关。HTG的遗传基础是异质性的，包括单基因和多基因形式。单基因HTG(MHTG)，又称1型高脂蛋白血症和家族性乳糜斑综合征，是一种罕见而严重的疾病，由富含甘油三酯的脂蛋白分解代谢相关基因的纯合子突变引起。多基因HTG(PHTG)更为普遍，被认为是多个基因杂合变异累积效应的结果，包括那些涉及mHTG的基因。我们发现脂肪酶成熟因子1(LMF1)突变是mHTG的罕见原因。虽然LMF1已经被描述为参与LPL和HL折叠的脂酶-链，但在内质网稳态中一个更广泛的作用正在出现。然而，由于缺乏可行的LMF1缺乏症动物模型，LMF1功能在体内的相关性仍然知之甚少。在目标1a中，我们将通过条件Lmf1基因敲除(cLmf1-KO)小鼠的发展和特征来解决这一知识差距。在LMF1缺陷患者中有效地治疗HTG仍然是一个主要的临床需求，因为传统的降脂药物在很大程度上是无效的基于基因的治疗，包括LPL基因替代和APOC3抑制为mHTG提供了有希望的机会。然而，由于几乎所有临床试验中的mHTG患者都存在LPL突变，评估LMF1缺陷患者的疗效是具有挑战性的。在目标1b中，我们将使用cLmf1-KO小鼠来评估基于基因的治疗方法在LMF1缺乏症中的潜在益处。虽然LMF1在mHTG中的作用已经确定，但我们的初步结果表明，杂合子LMF1变异也可能与pHTG有关。在目标2中，我们将通过评估pHTG相关LMF1变体对LPL成熟的功能影响和评估它们赋予LMF1基因的遗传负担来检验这一假设。总之，建议的研究将有助于更好地理解LMF1在单基因和多基因HTG中的作用，并为LMF1缺乏症的新治疗方法提供原则证据。

Primary hypertriglyceridemia (HTG) is a common clinical presentation of dyslipidemia characterized by abnormally elevated plasma TG level. HTG is associated with increased risk of cardiovascular disease and, in its severe manifestations, acute pancreatitis, eruptive xanthomas, lipemia retinalis and hepatosplenomegaly. The genetic basis of HTG is heterogeneous and includes monogenic and polygenic forms. Monogenic HTG (mHTG), also known as type 1 hyperlipoproteinemia and familial chylomicronemia syndrome, represents a rare and severe form of the condition and is caused by homozygous mutations in genes related to the catabolism of TG-rich lipoproteins. Polygenic HTG (pHTG) is more prevalent and thought to result from the cumulative effects of heterozygous variants in multiple genes, including those involved in mHTG. We identified mutations Lipase Maturation Factor 1 (LMF1) as a rare cause of mHTG. While LMF1 has been characterized as a lipase-chaprone involved in the folding of LPL and HL, a more general role in ER homeostasis is emerging. However, the in vivo correlates of LMF1 function remain poorly understood due to the lack of a viable animal model of LMF1 deficiency. In Aim 1a, we will address this knowledge gap through the development and characterization of conditional Lmf1-knockout (cLmf1-KO) mice. Effective management of HTG in LMF1-deficient patients remains an major unmet clinical need, because traditional lipid-lowering medications are largely ineffective Gene-based therapies including LPL gene-replacement and APOC3-suppression represent promising opportunities in mHTG. However, as virtually all mHTG patients in clinical trials harbor LPL mutations, the evaluation of therapeutic efficacy in LMF1-deficient patients is challenging. In Aim 1b, we will use cLmf1-KO mice to evaluate the potential benefits of gene-based therapeutic approaches in LMF1 deficiency. While the role of LMF1 in mHTG is well established, our preliminary results suggest that heterozygous LMF1 variants may also contribute to pHTG. In Aim 2, we will test this hypothesis by evaluating the functional impact of pHTG-associated LMF1 variants on LPL maturation and assessing the genetic burden they confer to the LMF1 gene. In conclusion, the proposed studies will lead to a better understanding of the role of LMF1 in monogenic and polygenic HTG and provide proof-of-principle for novel therapeutic approaches in LMF1 deficiency.