Metabolic diseases, such as type II diabetes (T2DM), atherosclerosis and other cardiovascular diseases, are prevalent and are important health issues in the modern world. T2DM contributes to the development of various metabolic diseases. Atherosclerosis is one of the major causes leading to multiple cardiovascular diseases. In order to develop therapeutic strategies, understanding the mechanisms of these metabolic diseases is crucial. It is known that the immune system is highly involved in initiation and progression of metabolic diseases. Macrophages are one of the major leukocytes in innate immunity. Macrophages have two major polarized phenotypes: classical/pro-inflammatory (M1) and alternative/anti-inflammatory (M2). It is widely accepted that M1-M2 switch in macrophage population is essential in disease progression or damage recovery; however, the detailed mechanism of macrophage phenotype switch has not been fully elucidated. In addition, the effect of altering the macrophage phenotype on treating metabolic diseases remains uncertain. Receptor-interacting protein 140 (RIP140) is a co-regulator of numerous nuclear receptors and transcription factors. RIP140 is expressed in various cell types including adipocytes, liver, muscle, heart, neurons, and cells in the monocyte–macrophage lineage. Studies showed that RIP140 expression is positively associated with the progression of metabolic disorders such as obesity, insulin resistance, and glucose intolerance. In addition, studies indicate that RIP140 acts as a co-activator of NFκB to promote macrophage M1 activation and pro-inflammatory responses. My studies further build on this knowledge to uncover the role of RIP140 in the metabolic diseases. First, it was found that RIP140 elevates cholesterol content in macrophages by reducing expression of ABC transporters, which are responsible for cholesterol efflux. The elevated cytosolic cholesterol induces foam cell formation and further enhances progression of atherosclerosis. This study indicated that reducing RIP140 levels effectively ameliorates high-cholesteroldiet-induced atherosclerosis. Second, my study found that reducing RIP140 in macrophages leads to macrophage M2 polarization, resulting in adipose tissue remodeling to brown/beige adipose tissue. This further ameliorates high fat diet-induced T2DM associated metabolic disorders. Moreover, later studies address how RIP140 mediates macrophage M2 activation and M1/M2 switch by its cytosolic function in a wound healing animal model. Final study is to identify a beneficial taxonomic repertoire from macrophage specific RIP140 knockdown (MφRIP140KD) mice. Fecal microbiota transplantation (FMT) from HFD-fed MφRIP140KD to wild type (WT) mice acquired the benefits from donors, which is resistant to development of HFD-induced metabolic diseases. Taken together, this thesis studies elucidate novel functions of RIP140 in polarization and inflammatory responses in macrophages, and identify the benefits of reducing RIP140 expression in macrophages. These findings contribute to our understanding of the relationship between immune and metabolic systems as well as provide a therapeutic target of resolving inflammation and preventing/improving metabolic profiles in T2DM, and atherosclerosis.
University of Minnesota Ph.D. dissertation. December 2016. Major: Pharmacology. Advisor: Li-Na Wei. 1 computer file (PDF); ix, 150 pages.
The Functional Role of Receptor-Interacting Protein 140 (RIP140) in Innate Immunity and Metabolic Syndrome.
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