The prevalence of metabolic diseases in modern society, including Type II diabetes mellitus (T2DM), hypertension and cardiovascular diseases, is a major burden on health care systems. Among these diseases, T2DM and its associated complications contribute to the progression of other metabolic diseases such as fatty liver diseases and atherosclerosis. Understanding the initiation and progression of T2DM is critical for developing treatments for T2DM and its associated metabolic disorders. Adipocyte dysfunctions and chronic inflammation have been shown recently to play essential roles in the progression of T2DM. Normally, adipocytes can store energy as triglycerides, fine-tune other metabolic tissues¡¦ lipid and glucose metabolism, and secreted cytokines (adipokines) to modulate immune response. In T2DM or obesity, adipocytes become dysfunctional, with increased lipolysis, an altered adipokine profile, and decreased insulin sensitivity and glucose uptake ability. These changes affect not only the adipocytes themself but also systemic glucose and lipid metabolism. In obese patients and in the high-fat diet (HFD)-fed mouse model, increased inflammatory response in macrophages also contributes to adipocyte dysfunction. The escalated inflammatory response plays pathophysiological roles in various metabolic disorders, including atherosclerosis and arthritis, and increases the incidence of septic shock. However, the underlying mechanisms for initiation of adipocyte dysfunctions and escalation of inflammatory response remain unclear.
Receptor-interacting protein 140 (RIP140) is a co-regulator for various transcription factors and nuclear receptors and is expressed mainly in macrophages and metabolic tissues, including adipocytes, hepatocytes and muscle cells. RIP140 affects the progression of T2DM through its nuclear activity as shown by the resistance of knockout mice to diet-induced diabetes and its associated metabolic disorders. In my studies, I found that when I used HFD feeding to induce T2DM, RIP140 could accumulate within the cytoplasm of adipocytes. I further demonstrated that cytoplasmic RIP140 not only interacted with AS160 to impede GLUT4 vesicle trafficking and adiponectin vesicle secretion, but also formed a complex with perilipin A to enhance lipolysis. These findings suggest that HFD feeding can alter RIP140¡¦s cellular distribution, which leads to adipocyte dysfunctions including higher lipolysis, lower glucose uptake, and reduction in adiponectin secretion. I also showed that HFD feeding promoted cytoplasmic accumulation of RIP140 in adipocytes through a PKCϵ-dependent signaling pathway by enhancing intracellular lipid content (as an intrinsic stimulus) and circulating endothelin-1 (as an extrinsic stimulus). Most importantly, administration of a selective ET-1 receptor anatagonist, ambrisentan, reduced HFD-induced cytoplasmic accumulation of RIP140 in adipocytes and further ameliorate hepatic steatosis and insulin sensitivity in vivo. These findings reveal the novel roles of cytoplasmic RIP140 in adipocyte dysfunctions and provide evidence for cytoplasmic RIP140 as a promising target for treatment of T2DM.
Recently, RIP140 has also been shown to affect proinflammatory cytokine production by functioning as co-activator for NF-<em>f</em>ÛB in macrophages. I showed that HFD feeding up-regulated RIP140 expression by promoting intracellular cholesterol level which led to increased proinflammatory potential in macrophages. In this study, intracellular cholesterol level regulates RIP140 expression by decreasing microRNA-33a, which targeted RIP140 via a conserved region in 3¡¦-UTR of RIP140 mRNA. I further discovered that TLR ligands could trigger RIP140 degradation to resolve inflammation. This RIP140 degradation was modulated by RelA-recruited SCF E3 ligase and Syk-mediated phosphorylation on RIP140. My studies in macrophages demonstrate that RIP140 in macrophages can be modulated by a HFD to affect the systemic inflammatory response and further suggest that defects in RIP140 degradation may cause non-resolving inflammation which is involved in septic shock and various metabolic disorders.
Taken together, my studies provide evidence for the novel functions of RIP140 in adipocyte dysfunction and inflammatory response in macrophages and determine the mechanisms by which HFD affect RIP140¡¦s distribution and expression in adipcoytes and macrophages. These findings contribute to our understanding of how HFD causes adipocyte dysfunctions and increase inflammatory response.
University of Minnesota Ph.D. dissertation. March 2012. Major: Pharmacology. Advisor: Dr. Li-Na Wei. 1 computer file (PDF); viii, 164 pages.
Functional role of receptor-interacting protein 140 (RIP140) in adipocyte dysfunctions and inflammatory response in macrophages..
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