Lipokines · The impact of bioactive lipokines on atherosclerosis

The impact of bioactive lipokines on atherosclerosis

The prevalence of obesity increased to epidemic proportions with little hope for effective treatments on the horizon. A major concern for global public health regarding the rise in obesity is the accompanying aggregation of co-morbidities, which includes insulin resistance, diabetes, hepatosteatosis, dyslipidemia, hypertension, coagulopathies and atherosclerosis (collectively referred to as the cardiometabolic syndrome). Research studies performed in the past decade showed that these chronic and complex diseases are profoundly influenced by pathways that lie at the interface of metabolism and inflammation. Despite intense research effort into illuminating the crosstalk between metabolic and inflammatory pathways, a gap in our knowledge remains regarding the nutritional modification of such crosstalk. What are the nutritional cues that can beneficially modify this crosstalk? Bioactive lipids offer tools to study this question in depth. In this study we addressed the potential of palmitoleate (PAO) for nutritional modification of the crosstalk between metabolism, inflammation and stress pathways in atherosclerosis. Discoveries arising from this study have important implications for understanding the pathogenesis of atherosclerosis and the generation of a novel therapeutic approach to this devastating disease. Recent studies have shown that bioactive lipid species released by metabolically active tissues can have profound effects on systemic metabolism. For example PAO, also known as a lipokine, can be generated from the adipose tissue through de novo lipogenesis and exert endocrine effects in distant tissues such as the liver and skeletal muscle and improve insulin sensitivity. Very little is known about PAO’s mechanism of action in vivo. PAO can suppress inflammation in the adipose tissue and improve insulin signaling in vitro and in vivo. Furthermore, PAO can prevent lipotoxic endoplasmic reticulum (ER) stress, a common pathophysiologial mechanism that drives obesity, insulin resistance, diabetes and atherosclerosis. The links between nutrient sensing-pathways, stress signaling and inflammation are central to atherogenesis and its complications, but very little is known about the nutritional modification of this crosstalk. Here, we investigated the impact of chronic PAO treatment on the atherosclerotic plaque progression. Using a mouse model of atherosclerosis (the apolipoprotein E deficient, ApoE-/- mice), we seeked to understand the impact of chronic and orally active PAO treatment on cell types that are central to atherogenesis such as macrophages and vascular smooth muscle. One of our main aims is to understand the impact of short and long term PAO treatment on atherosclerotic lesion formation and progression. We evaluate the impact of PAO on atherogenesis. Chronic and oral PAO treatment lead to a significant reduction in atherosclerotic lesions. We also evaluated in detail PAO’s effect on lesion composition in these experiments. PAO led to a reduction of macrophage and foam cell content in the lesions without significant changes in lesion T cell, vascular smooth muscle or collagen content. PAO lead to marked decrease in macrophage ER stress and apoptosis in lesions. We did not observe a significant alteration of systemic lipid and lipoprotein profiles with PAO intervention. Another goal of our studies has been to illuminate PAO’s mechanism of action in cells that play an important role in the pathogenesis of atherosclerosis. For this purpose, we have been studying PAO’s impact mainly on macrophages and the vascular smooth muscle. PAO can block lipid-induced (palmitate or PA) ER stress and apoptosis, while it has no effect on ER stress induced by acute luminal stress (tunicamycin) or calcium release (thapsigargin). Moreover, PAO leads to significant reduction in lesion ER stress. PAO has a significant anti-inflammatory effect in macrophages, including suppression of inflammatory cytokine production and blocking inflammasome activation induced by PA. Similarly, chronic PAO treatment blocks inflammasome activity in vivo resulting in reduced d secreted IL-1B in serum. Furthermore, PAO blocks PA-induced generation of reactive oxygen species from the mitochondria in both primary bone marrow derived macrophages and human THP1 cells as well as in vascular smooth muscle. PAO does not change macrophage foam cell formation in vitro. So, the reduction in foam cells in atherosclerotic plaques from PAO-treated mice appear to be due to either reduced number of macrophages in lesions or to a decrease in lipid accumulation in other cell types that occur in the plaques. Finally, we have carried out a lipidomic analysis in macrophages, which are genetically engineered to elevate PAO production. In these macrophages, we used a lipidomic approach to analyze the distribution of the newly synthesized PAO in the lipid classes. Based on this analysis one of the main destinations of PAO is the phospholipids class. Another intriguing observation was PAO’s incorporation to cardiolipin composition, suggesting active remodeling of mitochondrial inner membrane. Mitochondrial membrane remodeling combined with reduce mitochondrial ROS production after PAO treatment suggests PAO has significant impact on mitochondrial stress responses. In summary, the contribution of innate and adaptive immune response to the components of metabolic syndrome such as obesity, insulin resistance, diabetes and atherosclerosis has been widely demonstrated, however, the molecular mechanisms linking the metabolic stress to immune activation has remained elusive. Here, we demonstrate chronic PAO treatment can alleviate atherosclerosis in mice despite dyslipidemia. Findings from our studies could have important implications for understanding the pathogenesis of metabolic and inflammatory diseases such as atherosclerosis and diabetes and facilitate the generation of novel therapeutic approaches. As metabolic inflammation is a major contributor to a many chronic diseases including atherosclerosis, diabetes, hepatosteatosis, obesity, cancer, neurodegenerative diseases and aging, discoveries made through the proposed studies is expected to have a multidisciplinary impact.

Data: CORDIS, © European Union