Razani lab
Our Work
We have a particular interest in atherosclerotic macrophages, macrophage polarization, foam cell formation, adipose tissue metabolism, adipose tissue macrophages, liver metabolism, the autophagy-lysosome system, lysosomal biogenesis, lysosomal acidification, lysosomal acid lipase and lysosomal lipolysis, selective autophagy (particularly p62/SQSTM1), lipophagy, aggrephagy, mitophagy, mTOR signaling, differing roles of mTORC1 and mTORC2, nanoparticle delivery systems, and iPSC (induced pluripotent stem cells)
Cholesterol-mTOR Axis in Human Monocytes
Atherosclerosis is driven in part by impaired autophagy in macrophages, which leads to accumulation of damaged organelles and contributes to plaque formation. While existing cholesterol-lowering therapies reduce lipid levels, they do not directly restore autophagic function. Our study investigates how LDL cholesterol activates mTORC1, a key inhibitor of autophagy, in human monocyte-derived macrophages (HMDMs). We found that LDL robustly induces mTORC1, suppressing autophagy and promoting pro-atherogenic phenotypes. We are now examining mTORC1 activity in monocytes from both hypercholesterolemic patients and matched controls, before and after lipid-lowering therapy, to uncover potential therapeutic targets for restoring autophagy in cardiovascular disease.
Ali Ajam, MD, Director of Clinical Research in the Razani Lab, is leading a clinical study aimed at investigating how LDL cholesterol levels affect monocyte mTOR signaling in humans. The study recruits individuals with hypercholesterolemia as well as matched controls at UPMC. Blood samples are collected before and after 12 weeks of lipid-lowering therapy, followed by monocyte isolation and mTOR activity analysis. This research helps uncover how cholesterol metabolism intersects with mTOR-related inflammatory pathways.
Adipose Tissue Lysosomal Lipid Metabolism under Cold Exposure
Adipose tissue browning, a process of phenotypic switching by the white adipose tissue when subjected to specific stimuli such as cold exposure, is one of the major ways to enhance thermogenesis to maintain body temperature and metabolic homeostasis. Due to the propensity to metabolize instead of store lipids in adipose tissue, browning has been recently thought as an effective strategy to prevent or treat obesity and complications. However, the role of lysosomal function and lysosomal lipolysis in cold-induced browning and lipid metabolism remains unknown.
Dr. Yu-Sheng Yeh Findings include the following: studies the role of lysosomal acid lipase (LAL) in the hydrolysis of triglycerides and cholesteryl esters in lysosomes of adipocytes. His work supports the notion that adipose tissue is not only a storage depot for excess nutrients but a critically important endocrine gland.
1.Cold exposure triggers lysosomal and autophagic programs in adipocytes.
2.Lysosomal acid lipase has a high correlation with browning markers and plasma lipids.
3.Adipose lysosomal lipid metabolism is involved in browning of inguinal white adipose tissue.
4.Lysosomal acid lipase in adipose tissue is necessary for cold-induced thermogenesis and β-adrenergic agonist treatment-induced lipolysis
Project Coming Soon
Project description coming soon.
Project Coming Soon
Project description coming soon.
Association of Cardiovascular Risk with Leucine Activation of mTOR in Macrophages
Project description coming soon.
Very high-protein intake induces mTORC1 activation and inhibition of autophagy in isolated human monocytes
(A-D) Before and after consuming the low and very high protein meals, mTORC1 activation in isolated circulating monocytes was evaluated by (A,B) Western blot and (C) FACS analysis of phosphorylated ribosomal protein S6, and (D) co-localization of mTOR and LAMP2 by immunofluorescence (IF) microscopy. (E,F) IF microscopy analysis of LC3 autophagy marker in isolated circulating monocytes before and after consuming the low and very high protein meals. For all graphs, data are presented as mean ± SEM, n=14. **P < 0.01 and ***P < 0.001.