Abstract
The adipocyte is unique in its capacity to store lipids. In addition to triglycerides, the adipocyte stores a significant amount of cholesterol. Moreover, obese adipocytes are characterized by a redistribution of cholesterol with depleted cholesterol in the plasma membrane, suggesting that cholesterol perturbation may play a role in adipocyte dysfunction. We used methyl-β-cyclodextrin (MβCD), a molecule with high affinity for cholesterol, to rapidly deplete cholesterol level in differentiated 3T3-L1 adipocytes. We tested whether this perturbation altered adipocyte secretion of monocyte chemoattractant protein-1 (MCP-1), a chemokine that is elevated in obesity and is linked to obesity-associated chronic diseases. Depletion of cholesterol by MβCD increased MCP-1 secretion as well as the mRNA and protein levels, suggesting perturbation at biosynthesis and secretion. Pharmacological inhibition revealed that NF-κB, but not MEK, p38 and JNK, was involved in MβCD-stimulated MCP-1 biosynthesis and secretion in adipocytes. Finally, another cholesterol-binding drug, filipin, also induced MCP-1 secretion without altering membrane cholesterol level. Interestingly, both MβCD and filipin disturbed the integrity of lipid rafts, the membrane microdomains enriched in cholesterol. Thus, the depletion of membrane cholesterol in obese adipocytes may result in dysfunction of lipid rafts, leading to the elevation of proinflammatory signaling and MCP-1 secretion in adipocytes.
Highlights
The physiological function of adipose tissue is to store lipids
We tested whether cholesterol depletion affected adipocyte secretion of monocyte chemoattractant protein-1 (MCP-1), a chemokine involved in obesity-associated chronic diseases [17, 18]. 3T3-L1 adipocytes were treated without (Ctrl) or with MβCD for 4 hours, and MCP-1 secretion in the medium was measured by Enzyme-Linked Immunosorbent Assay (ELISA)
Simultaneous treatment of MβCD and tumor necrosis factor α (TNFα) did not suppress nor enhance the TNFα-induced MCP-1 secretion (Fig 1B). These results suggested that depletion of cholesterol by MβCD treatment increased MCP-1 secretion in adipocytes
Summary
The physiological function of adipose tissue is to store lipids. Excess energy intake results in the storage of triglyceride, a neutral lipid composed of esterified fatty acids and glycerol, in the lipid droplet of adipocytes. The unique form and significant amount of cholesterol in adipocytes suggest a possible role for cholesterol in regulating adipocyte function Both cholesterol and triglycerides are elevated and accumulated in hypertrophied adipocytes [2, 4]. Factors that prevent insulin resistance such as adiponectin and the anti-diabetic drug thiazolidinediones, down-regulate the secretion of MCP-1 in adipocytes [17] These observations suggest a link between the MCP-1 level, obesity, and insulin resistance. The disturbance of lipid raft integrity rather than the decrease of cellular or membrane cholesterol may account for the MβCD-mediated increase of MCP-1 expression and secretion. The depletion of membrane cholesterol in obese adipocytes may lead to the disturbance of lipid rafts, which results in elevated proinflammatory responses and production of proinflammatory cytokines and chemokines in obesity
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