Obesity and related diseases are major global health challenges, affecting both developed and developing nations and causing significant socioeconomic burdens. A key manifestation is metabolic dysfunction–associated steatotic liver disease (MASLD), in which lipids accumulate in tissues not designed for fat storage, such as the liver, muscle, and vasculature, creating a lipotoxic environment. MASLD affects roughly 25% of the global population and is closely linked to the metabolic syndrome, a cluster of disorders that substantially increases cardiovascular disease (CVD) risk. While lifestyle interventions such as caloric restriction and physical activity are central to management, morbidly obese patients often struggle to maintain weight loss, and very few effective licensed pharmacological therapies exist. Bariatric surgery provides sustained metabolic benefits but is suitable only for a subset of patients, highlighting the urgent need for alternative preventive strategies.
LIPIDEMIA addresses this challenge by investigating the early mechanisms of MASLD in the context of atherogenic dyslipidemia. Elevated apolipoprotein B (ApoB)-containing lipoproteins, particularly low-density lipoprotein (LDL), drive cardiovascular risk and contribute to MASLD pathogenesis. Conventional animal models often fail to replicate the human lipid profile, limiting the study of disease initiation and progression. To overcome these limitations, LIPIDEMIA has employed novel mouse models that can be rendered acutely dyslipidemic, allowing in vivo tracking of ApoB-lipoproteins and providing a platform to study MASLD onset under conditions closely mirroring human physiology.
The project aims to uncover targetable mechanisms for preventing MASLD and its cardiovascular complications. First, it defines the identity and role of resident liver macrophages, particularly Kupffer cell subsets, in initiating hepatic responses to dyslipidemia, and examine how macrophage depletion affects disease progression. Second, it better elucidates the role of lipid-loaded Kupffer cells and how they promote atherosclerosis at a distance. Third, it assesses the origins of hepatic lipid accumulation at disease onset, distinguishing between de novo lipogenesis and impaired lipid metabolism, using advanced nuclear magnetic resonance techniques to quantify newly synthesized triglycerides and cholesterol.
By combining innovative animal models, molecular and imaging techniques, and targeted interventions, LIPIDEMIA provides a clear pathway to impact. The project is expected to advance understanding of MASLD initiation, identify preventive strategies against atherogenic dyslipidemia, and ultimately reduce the burden of metabolic and cardiovascular diseases. Some of its findings have already been published in Nature Cardiovascular Research, and an additional manuscript is currently in preparation, highlighting the project’s potential for broad translational impact by informing both therapeutic development and public health strategies worldwide.
