Periodic Reporting for period 1 - LIPIDEMIA (Initiation Mechanisms of Lipid-driven Diseases)
Berichtszeitraum: 2023-11-01 bis 2025-10-31
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.
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.
We have carried out experiments addressing all the project objectives, adapting and refining them as necessary in response to emerging results and evolving research needs.
We have demonstrated that, in mice, Kupffer cells are able to uptake lipoproteins and trigger a transcriptional program that a high-fat diet alone cannot induce. Using electron microscopy, we observed that the morphology of Kupffer cells differs depending on the type of lipoprotein they process, highlighting distinct cellular pathways involved in lipoprotein handling. Metabolomics analysis further confirmed that livers overloaded with chylomicron remnants face different metabolic challenges compared to LDL-loaded livers. However, regardless of lipoprotein type, embryonically derived Kupffer cells inevitably undergo cell death after prolonged exposure to excess lipoproteins.
To investigate the role of lipid-loaded Kupffer cells, we engineered two novel mouse models that enable targeted and sustained Kupffer cell depletion under dyslipidemic conditions. Using one of these models, RNA sequencing of aortic tissue from dyslipidemic mice lacking Kupffer cells revealed transcriptional changes in vascular smooth muscle cells, particularly in pathways controlling extracellular matrix remodeling and phenotypic switching - key drivers of plaque development and stability. To identify the circulating factors responsible for these vascular changes, we conducted mass spectrometry analysis on mouse plasma, linking liver macrophage activity to distant vascular effects.
Moreover, Nuclear Magnetic Resonance (NMR) analyses demonstrated that the increase in liver triglycerides and cholesterol observed in dyslipidemic mice, even in the absence of a high-fat diet, is not driven by de novo synthesis. This finding suggests that alternative pathways, such as impaired VLDL export, may be responsible, and future studies will focus on elucidating these mechanisms.
We have demonstrated that, in mice, Kupffer cells are able to uptake lipoproteins and trigger a transcriptional program that a high-fat diet alone cannot induce. Using electron microscopy, we observed that the morphology of Kupffer cells differs depending on the type of lipoprotein they process, highlighting distinct cellular pathways involved in lipoprotein handling. Metabolomics analysis further confirmed that livers overloaded with chylomicron remnants face different metabolic challenges compared to LDL-loaded livers. However, regardless of lipoprotein type, embryonically derived Kupffer cells inevitably undergo cell death after prolonged exposure to excess lipoproteins.
To investigate the role of lipid-loaded Kupffer cells, we engineered two novel mouse models that enable targeted and sustained Kupffer cell depletion under dyslipidemic conditions. Using one of these models, RNA sequencing of aortic tissue from dyslipidemic mice lacking Kupffer cells revealed transcriptional changes in vascular smooth muscle cells, particularly in pathways controlling extracellular matrix remodeling and phenotypic switching - key drivers of plaque development and stability. To identify the circulating factors responsible for these vascular changes, we conducted mass spectrometry analysis on mouse plasma, linking liver macrophage activity to distant vascular effects.
Moreover, Nuclear Magnetic Resonance (NMR) analyses demonstrated that the increase in liver triglycerides and cholesterol observed in dyslipidemic mice, even in the absence of a high-fat diet, is not driven by de novo synthesis. This finding suggests that alternative pathways, such as impaired VLDL export, may be responsible, and future studies will focus on elucidating these mechanisms.
LIPIDEMIA has generated new mechanistic insights that reshape the understanding of how liver metabolism influences cardiovascular health. By integrating molecular, imaging, and lipidomic approaches, the project uncovered key communication pathways between hepatic macrophages and the vasculature, revealing that metabolic stress in the liver can trigger systemic inflammatory and vascular responses. These discoveries advance the current model of MASLD progression, establishing a direct mechanistic bridge between lipid handling in the liver and early vascular alterations linked to atherosclerosis.
The project’s outcomes create a strong foundation for translational research, providing new molecular targets and experimental models that can be applied by other groups to test preventive or therapeutic interventions. The knowledge generated through LIPIDEMIA not only strengthens the scientific basis for future funding initiatives but also contributes to a broader research framework within the metabolic and cardiovascular fields, stimulating collaborative efforts to address one of the most pressing health challenges of the coming decades.
To ensure the continued impact and legacy of LIPIDEMIA, it is essential to sustain and expand the research program. Building on the results achieved over the past two years, further studies are needed to fully elucidate the mechanisms by which Kupffer cells drive MASLD progression and cardiovascular risk. New grant applications, informed directly by LIPIDEMIA’s findings, have been submitted to secure funding for the next phase of the project. Continued support will enable LIPIDEMIA to translate its discoveries into deeper mechanistic understanding and potential therapeutic strategies, ensuring that the project’s advances are fully realized and further developed.
The project’s outcomes create a strong foundation for translational research, providing new molecular targets and experimental models that can be applied by other groups to test preventive or therapeutic interventions. The knowledge generated through LIPIDEMIA not only strengthens the scientific basis for future funding initiatives but also contributes to a broader research framework within the metabolic and cardiovascular fields, stimulating collaborative efforts to address one of the most pressing health challenges of the coming decades.
To ensure the continued impact and legacy of LIPIDEMIA, it is essential to sustain and expand the research program. Building on the results achieved over the past two years, further studies are needed to fully elucidate the mechanisms by which Kupffer cells drive MASLD progression and cardiovascular risk. New grant applications, informed directly by LIPIDEMIA’s findings, have been submitted to secure funding for the next phase of the project. Continued support will enable LIPIDEMIA to translate its discoveries into deeper mechanistic understanding and potential therapeutic strategies, ensuring that the project’s advances are fully realized and further developed.