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Open Access Publications from the University of California

Scholarly Works (36 results)

  • Article
  • Peer Reviewed
English Honors Theses (2024)
    Cover page: "The Beginning is hers, the ending, mine": Social Performance and Intergenerational Female Relationships in Works by Chang and Kingston
    • Thesis
    • Peer Reviewed
    UC San Diego Electronic Theses and Dissertations (2022)

    Obesity is an established risk factor for hypertension. Building upon the known fact that obesity-induced gut barrier breach leads to the leakage of various microbiota-derived products into host circulation and distal organs, this study seeks to explore impacts of microbial DNA enrichment on inducing obesity-related adrenomedullary abnormalities and hypertension. CRIg (Complement receptor of the immunoglobulin superfamily) abundance is identified as a major factor in blocking the infiltration of gut mEVs (microbial DNAcontaining extracellular vesicles) into the bloodstream and adrenal glands. In lean CRIg-/- or C3-/- mice intravenously injected with gut mEVs, adrenal microbial DNA accumulation elevated adrenal inflammation and norepinephrine secretion, concomitant with hypertension. In addition, microbial DNAs promoted inflammatory responses and norepinephrine production in PC12 cells treated with gut mEVs. Depletion of microbial DNA cargos markedly blunted the effects of gut mEVs. We also validated that activation of cGAS/STING signaling is required for the ability of microbial DNAs to trigger adrenomedullary dysfunctions in both in vivo and in vitro experiments. Restoring CRIg+ cells in obese mice decreased microbial DNA abundance, inflammation, and hypertension. The leakage of gut mEVs leads to adrenal enrichment of microbial DNAs that are pathogenic to induce obesityassociated adrenomedullary abnormalities and hypertension. Recovering CRIg+ macrophage population attenuate obesity-induced adrenomedullary disorders.

      Cover page: Microbial DNA enrichment promotes adrenomedullary inflammation, catecholamine secretion, and hypertension in obese mice
      • Thesis
      • Peer Reviewed
      UC San Diego Electronic Theses and Dissertations (2024)

      Iron is found within the cell as Fe3+, ferritin-bound iron, and Fe2+, intracellular labile iron, which can be readily used for a variety of cellular functions, especially in the mitochondria. Macrophages, a major site for iron storage and recycling, undergo significant metabolic changes upon activation. Here, we demonstrate that sequestration of the labile iron pool to the mitochondria is characteristic of the macrophage proinflammatory response. Using LPS to stimulate proinflammatory activation in bone marrow derived macrophage (BMDMs) and embryonic Kupffer cells (emKCs), we measured labile iron content and mitochondrial iron with specific probes detected by flow cytometry. The expression of key iron metabolism genes and proinflammatory cytokines were measured to assess the iron metabolism and proinflammatory responses of macrophages. Treatment with LPS in vitro and in vivo demonstrated increased the mitochondrial Fe2+ content, while the intracellular labile iron pool was decreased. The emKC population was decreased after LPS stimulation, but this effect was attenuated by depletion of ferritin. Other hepatic macrophage populations, Kupffer cell-like (KC-like) cells and recruited hepatic macrophages (RHMs), increased in response to LPS. Nrf2, a master regulator of redox homeostasis, which was repressed in emKCs but upregulated in KC-like cells and RHMs, may be key to understanding the differences in responses to LPS exhibited by these macrophage populations. Our results expand upon the interplay between iron homeostasis and the metabolic changes required for macrophage activation.

        • Article
        • Peer Reviewed
        UC San Diego Previously Published Works (2020)
        Chronic, unresolved tissue inflammation is a well-described feature of obesity, type 2 diabetes mellitus (T2DM) and other insulin-resistant states. In this context, adipose tissue and liver inflammation have been particularly well studied; however, abundant evidence demonstrates that inflammatory processes are also activated in pancreatic islets from obese animals and humans with obesity and/or T2DM. In this Review, we focus on the characteristics of immune cell-mediated inflammation in islets and the consequences of this with respect to β-cell function. In contrast to type 1 diabetes mellitus, the dominant immune cell type causing inflammation in obese and T2DM islets is the macrophage. The increased macrophage accumulation in T2DM islets primarily arises through local proliferation of resident macrophages, which then provide signals (such as platelet-derived growth factor) that drive β-cell hyperplasia (a classic feature of obesity). In addition, islet macrophages also impair the insulin secretory capacity of β-cells. Through these mechanisms, islet-resident macrophages underlie the inflammatory response in obesity and mechanistically participate in the β-cell hyperplasia and dysfunction that characterizes this insulin-resistant state. These findings point to the possibility of therapeutics that target islet inflammation to elicit beneficial effects on β-cell function and glycaemia.
          Cover page: The role of macrophages in obesity-associated islet inflammation and β-cell abnormalities
          • Article
          • Peer Reviewed
          UC San Diego Previously Published Works (2021)
          Obesity induces an adaptive expansion of β cell mass and insulin secretion abnormality. Expansion of adipose tissue macrophages (ATMs) is a hallmark of obesity. Here, we assessed a novel role of ATMs in mediating obesity-induced β cell adaptation through the release of miRNA-containing extracellular vesicles (EVs). In both in vivo and in vitro experiments, we show that ATM EVs derived from obese mice notably suppress insulin secretion and enhance β cell proliferation. We also observed similar phenotypes from human islets after obese ATM EV treatment. Importantly, depletion of miRNAs blunts the effects of obese ATM EVs, as evidenced by minimal effects of obese DicerKO ATM EVs on β cell responses. miR-155 is a highly enriched miRNA within obese ATM EVs and miR-155 overexpressed in β cells impairs insulin secretion and enhances β cell proliferation. In contrast, knockout of miR-155 attenuates the regulation of obese ATM EVs on β cell responses. We further demonstrate that the miR-155-Mafb axis plays a critical role in controlling β cell responses. These studies show a novel mechanism by which ATM-derived EVs act as endocrine vehicles delivering miRNAs and subsequently mediating obesity-associated β cell adaptation and dysfunction.
            Cover page: Adipose Tissue Macrophages Modulate Obesity-Associated β Cell Adaptations through Secreted miRNA-Containing Extracellular Vesicles
            • Article
            Recent Work (2021)
            Summaries by Nobel laureate Kenneth J. Arrow of his 1962 lectures on general equilibrium theory at Northwestern University.   These summaries were widely circulated but unpublished.  Reissued here, edited with updated notation. With permission of the Arrow family.
              Cover page: Lectures on the Theory of Competitive Equilibrium
              • Article
              • Peer Reviewed
              UC San Diego Previously Published Works (2020)
              Chronic, unresolved tissue inflammation is a well-described feature of obesity, type 2 diabetes mellitus (T2DM) and other insulin-resistant states. In this context, adipose tissue and liver inflammation have been particularly well studied; however, abundant evidence demonstrates that inflammatory processes are also activated in pancreatic islets from obese animals and humans with obesity and/or T2DM. In this Review, we focus on the characteristics of immune cell-mediated inflammation in islets and the consequences of this with respect to β-cell function. In contrast to type 1 diabetes mellitus, the dominant immune cell type causing inflammation in obese and T2DM islets is the macrophage. The increased macrophage accumulation in T2DM islets primarily arises through local proliferation of resident macrophages, which then provide signals (such as platelet-derived growth factor) that drive β-cell hyperplasia (a classic feature of obesity). In addition, islet macrophages also impair the insulin secretory capacity of β-cells. Through these mechanisms, islet-resident macrophages underlie the inflammatory response in obesity and mechanistically participate in the β-cell hyperplasia and dysfunction that characterizes this insulin-resistant state. These findings point to the possibility of therapeutics that target islet inflammation to elicit beneficial effects on β-cell function and glycaemia.
                Cover page: The role of macrophages in obesity-associated islet inflammation and β-cell abnormalities
                • Article
                • Peer Reviewed
                UC San Diego Previously Published Works (2022)

                Aim

                Low-grade inflammation is the hallmark of non-alcoholic fatty liver diseases (NAFLD) and non-alcoholic steatohepatitis (NASH). The leakage of microbiota-derived products can contribute to liver inflammation during NAFLD/NASH development. Here, we assessed the roles of gut microbial DNA-containing extracellular vesicles (mEVs) in regulating liver cellular abnormalities in the course of NAFLD/NASH.

                Methods

                We performed studies with Vsig4-/- , C3-/- , cGAS-/- , and their wild-type littermate mice. Vsig4+ macrophage population and bacterial DNA abundance were examined in both mouse and human liver by either flow cytometric or immunohistochemistry analysis. Gut mEVs were adoptively transferred into Vsig4-/- , C3-/- , cGAS-/- , or littermate WT mice, and hepatocyte inflammation and HSC fibrogenic activation were measured in these mice.

                Results

                Non-alcoholic fatty liver diseases and non-alcoholic steatohepatitis development was concomitant with a diminished liver Vsig4+ macrophage population and a marked bacterial DNA enrichment in both hepatocytes and HSCs. In the absence of Vsig4+ macrophages, gut mEVs translocation led to microbial DNA accumulation in hepatocytes and HSCs, resulting elevated hepatocyte inflammation and HSC fibrogenic activation. In contrast, in lean WT mice, Vsig4+ macrophages remove gut mEVs from bloodstream through a C3-dependent opsonization mechanism and prevent the infiltration of gut mEVs into hepatic cells. Additionally, Vsig4-/- mice more quickly developed significant liver steatosis and fibrosis than WT mice after Western diet feeding. In vitro treatment with NASH mEVs triggered hepatocyte inflammation and HSC fibrogenic activation. Microbial DNAs are key cargo for the effects of gut mEVs by activating cGAS/STING.

                Conclusion

                Accumulation of microbial DNAs fuels the development of NAFLD/NASH-associated liver abnormalities.
                  Cover page: Microbial DNA enrichment promotes liver steatosis and fibrosis in the course of non‐alcoholic steatohepatitis
                  • Article
                  • Peer Reviewed
                  UC San Diego Previously Published Works (2021)
                  Exosomes are nanoparticles secreted by all cell types and are a large component of the broader class of nanoparticles termed extracellular vesicles (EVs). Once secreted, exosomes gain access to the interstitial space and ultimately the circulation, where they exert local paracrine or distal systemic effects. Because of this, exosomes are important components of an intercellular and intraorgan communication system capable of carrying biologic signals from one cell type or tissue to another. The exosomal cargo consists of proteins, lipids, miRNAs, and other RNA species, and many of the biologic effects of exosomes have been attributed to miRNAs. Exosomal miRNAs have also been used as disease biomarkers. The field of exosome biology and metabolism is rapidly expanding, with new discoveries and reports appearing on a regular basis, and it is possible that potential therapeutic approaches for the use of exosomes or miRNAs in metabolic diseases will be initiated in the near future.
                    Cover page: Exosomes as mediators of intercellular crosstalk in metabolism
                    • Article
                    • Peer Reviewed
                    UC San Diego Previously Published Works (2022)
                    Various microbial products leaked from gut lumen exacerbate tissue inflammation and metabolic disorders in obesity. Vsig4+ macrophages are key players preventing infiltration of bacteria and their products into host tissues. However, roles of islet Vsig4+ macrophages in the communication between microbiota and β cells in pathogenesis of obesity-associated islet abnormalities are unknown. Here, we find that bacterial DNAs are enriched in β cells of individuals with obesity. Intestinal microbial DNA-containing extracellular vesicles (mEVs) readily pass through obese gut barrier and deliver microbial DNAs into β cells, resulting in elevated inflammation and impaired insulin secretion by triggering cGAS/STING activation. Vsig4+ macrophages prevent mEV infiltration into β cells through a C3-dependent opsonization, whereas loss of Vsig4 leads to microbial DNA enrichment in β cells after mEV treatment. Removal of microbial DNAs blunts mEV effects. Loss of Vsig4+ macrophages leads to microbial DNA accumulation in β cells and subsequently obesity-associated islet abnormalities.
                      Cover page: Accumulation of microbial DNAs promotes to islet inflammation and β cell abnormalities in obesity in mice
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