Atherosclerosis involves interactions between inflammation system and dyslipidemia. MCPIP1 (Monocyte Chemotactic Protein induced Protein-1) is induced by proinflammatory molecules and serves as a negative feedback loop in regulating inflammatory responses. Our current study was designed to test the role of MCPIP1 in maintaining lipid homeostasis, the latter a pivotal factor that contributes to the pathogenesis of atherosclerosis. We found that MCPIP1 knockout mice displayed a decrease in levels of serum HDL-cholesterol and total triglycerides but an increase in serum LDL/VLDL-cholesterol levels when compared to wild-type mice. Additionally, ApoA-1 expression was reduced but LPL expression was upregulated in plasma from MCPIP1 knockout mice. The livers from the MCPIP1 knockout mice revealed a decrease in hepatocyte number and an increase in collagen deposition when compared to wild-type mice. These findings suggest that MCPIP1 deficiency can induce liver fibrosis, alter the expression of lipoproteins, and affect transportation and metabolism of lipids, indicating that MCPIP1 is involved in maintaining lipid homeostasis, possibly via negatively regulating inflammatory responses.

Background: Inflammation is considered to be a major initiator to angioplasty-induced vascular restenosis. Proinflammatory cytokines stimulate vascular smooth muscle cell (VSMC) migration and proliferation leading to neointimal hyperplasia. It has been reported that chronic caffeine use suppresses the production of proinflammatory cytokine TNF-a (tumor necrosis factor Alpha) and alters adenosine receptor expression in human neutrophils, indicating that caffeine may attenuate vascular injury-induced inflammation and subsequent neointimal hyperplasia. Our current study was designed to test the hypothesis that chronic caffeine treatment decreases vascular injuryinduced neointimal hyperplasia by suppressing VSMC migration and proliferation. Methods and Results: The experiments were carried out using both in vivo (rat carotid artery injury model) and in vitro (VSMCs isolated from rat aorta) models. Male Sprague-Dawley rats that received chronic caffeine treatment (10 and 20 mg/kg per day, through oral gavage) showed a significant decrease in neointimal hyperplasia when compared to rats that received vehicle. To understand the underlying mechanisms, we tested if caffeine inhibits fetal bovine serum (FBS)-induced VSMC migration and proliferation. We found that caffeine substantially suppressed FBS-induced VSMC migration and proliferation. The attenuation of FBS-stimulated cell migration is dose dependent. Conclusion: Together, our results suggest that chronic treatment with high concentrations of caffeine attenuates vascular injury-induced neointimal hyperplasia by suppressing smooth muscle cell migration and proliferation in rats.

Background:Increased inflammation is associated with alterations of lipid and lipoprotein metabolism. Recent studies suggest that MCPIP1 (Monocyte Chemotactic Protein induced Protein‐1) may have a role in maintaining normal metabolic balance by negatively regulating chronic inflammation. Our preliminary data revealed that the MCPIP1 deficient (MCPIP1‐/‐) mice have reduced body lipid deposits compared to control mice. The current project was designed to test if MCPIP1 is involved in maintaining lipid homeostasis by affecting hepatic lipid production and distribution. Methods: MCPIP1‐/‐ mice (C57/BL6 background, 6 weeks old) were identified by PCR. The serum and liver from control and MCPIP1‐/‐ mice were collected after fasting. Serum lipids (LDL/VLDL‐cholesterol and total triglyceride) and liver lipids (total cholesterol and triglyceride) were measured using commercially available kits. Results: The data collected from sixteen samples (eight control and eight MCPIP1‐/‐) showed that in MCPIP1 ‐/‐ mice the mean serum HDL‐cholesterol and total triglyceride concentrations were about 49% and 31% lower respectively, compared to control mice. In contrast, serum concentration of LDL/VLDL‐cholesterol in MCPIP1‐/‐ mice increased about 66% when compared to control. Triglyceride in the liver tissue of MCPIP‐/‐ mice was also drastically decreased (72% lower than control). No changes were observed in total cholesterol in liver tissue. Conclusion: The lack of MCPIP1 is associated with alterations of lipid homeostasis. Grant Funding Source: Supported by KCOM Graduate Program in Biomedical Sciences

Emerging evidence suggests that elevated inflammatory/immune events are associated with pathogenesis of diabetes. MCPIP1 (monocyte chemotactic protein [MCP]–induced protein 1; also known as ZC3H12A), an immune response modifier expressed in mice macrophage in response to LPS and MCP‐1 stimulation, plays a negative role in the process of inflammation. Our current study was designed to test if MCPIP‐1 deficiency induced metabolic dysfunction by affecting the insulin signaling transduction pathway. Wild‐type C57/BL6 mice and MCPIP‐1 knockout mice with the C57/BL6 background were used. We found that MCPIP‐1‐deficient mice showed severe hepatic inflammation and remodeling, lower fasting plasma insulin levels (p<0.05), delayed response to the glucose challenge (p<0.05), and reduced insulin tolerance (p<0.05). Our results also revealed that insulin‐induced phosphorylation of insulin receptor (IR), insulin receptor substrate 1(IRS‐1), and AKT were substantially decreased in the liver from MCPIP1‐deficient mice. In conclusion, MCPIP‐1 deficiency impairs insulin production, insulin signaling transduction, and the ability of enduring metabolic challenges by inducing hepatic inflammation.Funded by Warner's grant, A.T. Still University of Health Sciences.