LIPA as a promising target to fight cardiometabolic diseases – LIPOCAMD

Background: The metabolic syndrome defines a group of criteria confering high cardiovascular risk in patients, and represents one of the major public health challenges worldwide. Chronic low-grade inflammation as a common feature in this syndrome has been associated with excess adipose tissue. Thus, one challenge aspect of metabolic syndrome is to understand the cellular mechanisms linking low-grade inflammation to metabolic abnormalities that later generate clinical diseases. Lysosomal acid lipase (LIPA) is an acid hydrolase enzyme that breaks down fatty material (cholesteryl esters, CE and triglycerides, TG) within the lysosomal compartment of the cells and its activity has been reported to be decreased in the metabolic syndrome. Mutations in LIPA are the cause of a rare disease named Cholesteryl Ester Storage Disease (CESD) characterized by increased plasma level of pro-atherogenic lipoproteins. Observational studies in preclinical mouse models also suggest that Lipa deficiency causes an inflammatory phenotype characterized by macrophage-mediated inflammation, myelopoiesis and pathogenic leukocyte tissue infiltration inflammation resembling to key features of the metabolic syndrome.
Hypothesis: LIPA-dependent inflammation is central to cardiometabolic diseases.
Aims: The goal of the proposed research is to determine the role of LIPA in 1) macrophage inflammation, 2) adipocyte lipophagy as a central link to adipose tissue infllammation and 3) identify novel regulatory pathways for LIPA.
Methods: Based on our preliminary data and respective expertises, we will use gain/loss of function in cellular systems, tissue-specific mice models and translational studies in CESD patients to investigate in Task 1, the molecular mechanisms that regulate the inflammatory response in Lipa-deficient or overexpressing macrophages (Aim. 1) and the contribution of LIPA to the low-grade inflammation associated to cardiometabolic diseases taking advantage of preclinical and translational research (Aim. 2). In Task 2, the contribution of LIPA to adipocyte homeostasis (Aim. 1) and adipose tissue adipocyte/macrophage cross talk to cardiometabolic diseases (Aim. 2) will next be investigated. Finally, we will focus on identifying novel regulatory pathways for LIPA in Task 3, focusing on the interplay between the transcriptional factors TCBEF and IRF4 in vitro (Aim. 1) and in vivo (Aim. 2). Through transnational collaborations we will define in depth inflammatory profiles in CESD patients with partial LIPA deficiency.
Perspectives: A better understanding of the regulation and the role of LIPA in inflammation could lead to the ameliorate stratification of patients with cardiometabolic risks and identify novel promising targets to fight cardiometabolic diseases.