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.