Biology subjects

Karakashian, A.

Publications and source records attributed to Karakashian, A..

2 recordsLinked to original sources

bioRxiv2025

Impaired Chylomicron Secretion Results in Reduced Body Fat and Increased Intestinal Fatty Acid Oxidation by Activation of Autophagy

Intestinal absorption of dietary lipid is essential for systemic lipid homeostasis; however, elevated postprandial plasma lipid levels are associated with obesity and increased risk for atherosclerotic cardiovascular disease. In humans and rodents, biological sex impacts dietary triglyceride absorption and males tend to have higher postprandial triglyceride levels compared to females, but the physiological basis for this is not well understood. Here, we show that the gene DENND5B is associated with body composition in humans and mice and that genetic deletion of Dennd5b in mice prevents postprandial plasma triglyceride elevations in both sexes. Our findings establish a role for this protein in intestinal chylomicron secretion and reveal a biological sex-biased differential impact of its deletion on body composition, dietary fatty acid uptake, and intestinal metabolism. Mechanistically, our findings implicate autophagy and mitochondrial beta oxidation in coping with enterocyte lipid accumulation due to impaired chylomicron secretion. This work extends the emerging concept that the intestinal epithelium may play a prominent role in oxidation of diet-derived fatty acids and suggests that this process may contribute to biological sex-based differences in postprandial lipemia and body composition. HighlightsO_LIThe DENND5B gene is required for dietary triglyceride absorption and is associated with metabolic phenotypes in humans and mice. C_LIO_LIDisruption of chylomicron secretion differentially affects body composition, dietary lipid absorption, and intestinal metabolic activity in male and female mice. C_LIO_LIIn mice, genetic disruption of Dennd5b results in lower body fat in both sexes, and increased lean mass only in males. C_LIO_LIMetabolic phenotypes in Dennd5b-deficient mice are driven by reduced absorption of dietary lipid characterized by enterocyte lipid retention and increased fecal lipid excretion. C_LIO_LIImpaired chylomicron secretion in Dennd5b-/- mice induces autophagy-mediated disposal of cellular triglyceride and increased fatty acid oxidation in intestinal tissue. C_LI

physiology↗

bioRxiv2023

Enhancement of High-Density Lipoprotein-Associated Protease Inhibitor Activity Prevents Atherosclerosis Progression

BackgroundInflammatory cells within atherosclerotic lesions secrete various proteolytic enzymes that contribute to lesion progression and destabilization, increasing the risk for an acute cardiovascular event. The relative contributions of specific proteases to atherogenesis is not well understood. Elastase is a serine protease, secreted by macrophages and neutrophils, that may contribute to the development of unstable plaque. We have previously reported interaction of endogenous protease-inhibitor proteins with high-density lipoprotein (HDL), including alpha-1-antitrypsin, an inhibitor of elastase. These findings support a potential role for HDL as an endogenous modulator of protease activity. In this study, we test the hypothesis that enhancement of HDL-associated elastase inhibitor activity is protective against atherosclerotic lesion progression. MethodsWe designed an HDL-targeting protease inhibitor (HTPI) that binds to HDL and confers elastase inhibitor activity. Lipoprotein binding and the impact of HTPI on atherosclerosis was examined using mouse models. ResultsHTPI is a small (1.6 kDa) peptide with an elastase inhibitor domain, a soluble linker, and an HDL-targeting domain. When incubated with human plasma ex vivo, HTPI predominantly binds to HDL. Intravenous administration of HTPI to mice resulted in its binding to plasma HDL and increased elastase inhibitor activity on isolated HDL. Accumulation of HTPI within plaque was observed after systemic administration to Apoe-/- mice. To examine the effect of HTPI treatment on atherosclerosis, prevention and progression studies were performed using Ldlr-/- mice fed Western diet. In both study designs, HTPI-treated mice had reduced lipid deposition in plaque. Histology and immunofluorescence staining of aortic root sections were used to examine the impact of HTPI on lesion morphology and inflammatory features. ConclusionsThese data support the hypothesis that HDL-associated anti-elastase activity can improve the atheroprotective potential of HDL and highlight the potential utility of HDL enrichment with anti-protease activity as an approach for stabilization of atherosclerotic lesions.

physiology↗