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Open Access Publications from the University of California

Scholarly Works (49 results)

  • Article
  • Peer Reviewed
UC Davis Previously Published Works (2015)
Metabolic homeostasis requires integration of complex signaling networks which, when deregulated, contribute to metabolic syndrome and related disorders. Protein-tyrosine phosphatase 1B (PTP1B) has emerged as a key regulator of signaling networks that are implicated in metabolic diseases such as obesity and type 2 diabetes. In this review, we examine mechanisms that regulate PTP1B-substrate interaction, enzymatic activity and experimental approaches to identify PTP1B substrates. We then highlight findings that implicate PTP1B in metabolic regulation. In particular, insulin and leptin signaling are discussed as well as recently identified PTP1B substrates that are involved in endoplasmic reticulum stress response, cell-cell communication, energy balance and vesicle trafficking. In summary, PTP1B exhibits exquisite substrate specificity and is an outstanding pharmaceutical target for obesity and type 2 diabetes.
    Cover page: Protein-tyrosine phosphatase 1B substrates and metabolic regulation
    • Thesis
    • Peer Reviewed
    UC Davis Electronic Theses and Dissertations (2024)

    Alzheimer's disease is the most common form of dementia, and its prevalence is increasing worldwide. Therefore, understanding the disease's pathogenesis is of utmost importance. To this end, we performed untargeted metabolomic assays and targeted qPCR on postmortem visual cortex tissue from subjects diagnosed as cognitively normal control (Ctrl), mildly cognitively impaired (MCI), or with Alzheimer’s disease (AD). The subjects were closely split by sex, had comparable post-mortem intervals, were all Caucasian, and none were diagnosed with metabolic disease. The metabolomic assay revealed an upregulation in multiple metabolites in the glycogen synthesis and glycolysis pathways in the AD subjects. To further probe these findings, we generated heat maps and found a reduction in acetyl-CoA in the AD group. When evaluating the mRNA expression of key GLUTs in the CNS, we found a decrease in the AD group compared to the others. The AD groups also had a reduction in mRNA expression of key rate-limiting enzymes in the glycolytic pathway. Furthermore, we compared key energy metabolites and found that NADH, NAD+, and FAD were all reduced in the AD group compared to the MCI group. Lastly, we evaluated the mRNA expression of key proteins regulating insulin signaling. There was an increase in the mRNA expression of protein tyrosine phosphatase 1B and Src homology 2 domain-containing protein tyrosine phosphatases, and a decrease in the insulin degradation enzyme. In conclusion, the visual cortex tissue of the AD subjects demonstrates a shift in the metabolites involved in glucose metabolism and energy availability, a reduction in the mRNA expression of enzymes that break down glucose, and a shift in mRNA expression of enzymes that regulate insulin signaling in a way that promotes insulin resistance. Our results corroborate other laboratory’s findings and suggest that improving metabolic status may be a promising therapeutic strategy for treating AD.

      • Article
      • Peer Reviewed
      UC Davis Previously Published Works (2022)
      Diabetic nephropathy (DN) is a significant complication of diabetes and the leading cause of end-stage renal disease. Hyperglycemia-induced dysfunction of the glomerular podocytes is a major contributor to the deterioration of renal function in DN. Previously, we demonstrated that podocyte-specific disruption of the Src homology phosphatase 2 (Shp2) ameliorated lipopolysaccharide-induced renal injury. This study aims to evaluate the contribution of Shp2 to podocyte function under hyperglycemia and explore the molecular underpinnings. We report elevated Shp2 in the E11 podocyte cell line under high glucose and the kidney under streptozotocin- and high-fat diet-induced hyperglycemia. Consistently, Shp2 disruption in podocytes was associated with partial renoprotective effects under hyperglycemia, as evidenced by the preserved renal function. At the molecular level, Shp2 deficiency was associated with altered renal insulin signaling and diminished hyperglycemia-induced renal endoplasmic reticulum stress, inflammation, and fibrosis. Additionally, Shp2 knockdown in E11 podocytes mimicked the in vivo deficiency of this phosphatase and ameliorated the deleterious impact of high glucose, whereas Shp2 reconstitution reversed these effects. Moreover, Shp2 deficiency attenuated high glucose-induced E11 podocyte migration. Further, we identified the protein tyrosine kinase FYN as a putative mediator of Shp2 signaling in podocytes under high glucose. Collectively, these findings suggest that Shp2 inactivation may afford protection to podocytes under hyperglycemia and highlight this phosphatase as a potential target to ameliorate glomerular dysfunction in DN.
        Cover page: Deficiency of the Src homology phosphatase 2 in podocytes is associated with renoprotective effects in mice under hyperglycemia
        • Article
        • Peer Reviewed
        UC Davis Previously Published Works (2024)
        Trans vaccenic acid (TVA, trans11-18 : 1) and cis9, trans11-CLA (also known as rumenic acid; RA) have received widespread attention as potentially beneficial trans-FA due to their putative health benefits, including anti-diabetic properties. The objective of this study was to determine the effects of beef fat naturally enriched with TVA and RA on parameters related to glucose homoeostasis and associated metabolic markers in diet-induced obese (DIO) mice. Thirty-six male C57BL/6J mice (8 weeks old) were fed for 19 weeks with either a control low-fat diet (CLF), a control high-fat diet (CHF), or a TVA+RA-enriched high-fat diet (EHF). Compared with CLF, feeding either CHF or EHF resulted in adverse metabolic outcomes associated with high-fat diets, including adiposity, impaired glucose control and hepatic steatosis. However, the EHF diet induced a significantly higher liver weight TAG content and elevated plasma alanine transaminase levels compared with the CHF diet. Collectively, the findings from this study suggest that EHF does not improve glucose tolerance and worsens liver steatosis in DIO mice. However, the adverse effects of EHF on the liver could be in part related to the presence of other trans-FA in the enriched beef fat.
          Cover page: Effects of beef fat enriched with trans vaccenic acid and cis9, trans11-CLA on glucose homoeostasis and hepatic lipid accumulation in high-fat diet-induced obese mice.
          • Article
          • Peer Reviewed
          UC Davis Previously Published Works (2015)
          Acute pancreatitis (AP) is an inflammatory disease, and is one of the most common gastrointestinal disorders worldwide. Soluble epoxide hydrolase (sEH; encoded by Ephx2) deficiency and pharmacological inhibition have beneficial effects in inflammatory diseases. Ephx2 whole-body deficiency mitigates experimental AP in mice, but the suitability of sEH pharmacological inhibition for treating AP remains to be determined. We investigated the effects of sEH pharmacological inhibition on cerulein- and arginine-induced AP using the selective sEH inhibitor 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU), which was administered before and after induction of pancreatitis. Serum amylase and lipase levels were lower in TPPU-treated mice compared with controls. In addition, circulating levels and pancreatic mRNA of the inflammatory cytokines tumor necrosis factor-α, interleukin Il-1β, and Il-6 were reduced in TPPU-treated mice. Moreover, sEH pharmacological inhibition before and after induction of pancreatitis was associated with decreased cerulein- and arginine-induced nuclear factor-κB inflammatory response, endoplasmic reticulum stress, and cell death. sEH pharmacological inhibition before and after induction of pancreatitis mitigated cerulein- and arginine-induced AP. This work suggests that sEH pharmacological inhibition may be of therapeutic value in acute pancreatitis.
            Cover page: Soluble Epoxide Hydrolase Pharmacological Inhibition Ameliorates Experimental Acute Pancreatitis in Mice
            • Article
            • Peer Reviewed
            UC Davis Previously Published Works (2014)
            There is a need to identify strategies for type 2 diabetes prevention. Therefore, we investigated the efficacy of pioglitazone and alogliptin alone and in combination to prevent type 2 diabetes onset in UCD-T2DM rats, a model of polygenic obese type 2 diabetes. At 2 months of age, rats were divided into four groups: control, alogliptin (20 mg/kg per day), pioglitazone (2.5 mg/kg per day), and alogliptin+pioglitazone. Non-fasting blood glucose was measured weekly to determine diabetes onset. Pioglitazone alone and in combination with alogliptin lead to a 5-month delay in diabetes onset despite promoting increased food intake and body weight (BW). Alogliptin alone did not delay diabetes onset or affect food intake or BW relative to controls. Fasting plasma glucose, insulin, and lipid concentrations were lower and adiponectin concentrations were threefold higher in groups treated with pioglitazone. All treatment groups demonstrated improvements in glucose tolerance and insulin secretion during an oral glucose tolerance test with an additive improvement observed with alogliptin+pioglitazone. Islet histology revealed an improvement of islet morphology in all treatment groups compared with control. Pioglitazone treatment also resulted in increased expression of markers of mitochondrial biogenesis in brown adipose tissue and white adipose tissue, with mild elevations observed in animals treated with alogliptin alone. Pioglitazone markedly delays the onset of type 2 diabetes in UCD-T2DM rats through improvements of glucose tolerance, insulin sensitivity, islet function, and markers of adipose mitochondrial biogenesis; however, addition of alogliptin at a dose of 20 mg/kg per day to pioglitazone treatment does not enhance the prevention/delay of diabetes onset.
              Cover page: Administration of pioglitazone alone or with alogliptin delays diabetes onset in UCD-T2DM rats
              • Article
              • Peer Reviewed
              UC Davis Previously Published Works (2019)
              In the normal physiological state, intestinal epithelial cells act as a defensive frontline of host mucosal immunity to tolerate constant exposure to external stimuli. In this study, we investigated the potential anti-inflammatory and gut permeability protective effects of Laminaria japonica (LJ) water extract (LJE) and three types of fermented Laminaria japonica water extracts (LJE-F1, LJE-F2, and LJE-F3) in lipopolysaccharide (LPS)-stimulated Caco-2, human intestinal epithelial cells. All four extracts significantly decreased the production of nitric oxide and interleukin-6 induced by LPS stimulus. In addition, LJE and the three types of LJE-Fs also inhibited LPS-induced loss of monolayer permeability, as assessed by changes in transepithelial electrical resistance. All four LJ extracts significantly prevented the inhibition of the protein levels of occludin, whereas LJE, LJE-F1, and LJE-F3 significantly attenuated the reduction in phosphorylation of adenosine monophosphate-activated protein kinase compared with the LPS-treated group in Caco-2 cells. In conclusion, LJE and its fermented water extracts appear to have potential gut health-promoting effects by reducing inflammation and partially regulating the tight junction-related proteins in human intestinal epithelial cells. Thus, additional studies are warranted to evaluate Laminaria japonica as a therapeutic agent for inflammatory bowel diseases.
                Cover page: Laminaria japonica Extract Enhances Intestinal Barrier Function by Altering Inflammatory Response and Tight Junction-Related Protein in Lipopolysaccharide-Stimulated Caco-2 Cells
                • Article
                • Peer Reviewed
                UC Davis Previously Published Works (2013)
                Abstract Background Protein-tyrosine phosphatase 1B (PTP1B) is a physiological regulator of insulin signaling and adiposity and is a drug target for the treatment of obesity and diabetes. The molecular mechanisms underlying PTP1B metabolic actions require additional investigation. Results Herein, we identify Munc18c as a novel PTP1B substrate in adipocytes and in vivo. We demonstrate nutritional regulation of Munc18c in adipose tissue revealing decreased expression upon high fat feeding. In addition, PTP1B deficiency leads to elevated Munc18c tyrosine phosphorylation and dissociation from syntaxin4. At the molecular level, we identify Munc18c Tyr218/219 and Tyr521 as key residues that mediate Munc18c interaction with PTP1B. Further, we uncover an essential role of Munc18c total tyrosine phosphorylation in general, and Tyr218/219 and Tyr521 in particular, in regulating its interactions and glucose uptake in adipocytes. Conclusion In conclusion, our findings identify PTP1B as the first known tyrosine phosphatase for Munc18c and a regulator of its phosphorylation and function in adipocytes.
                  Cover page: Regulation of the SNARE-interacting protein Munc18c tyrosine phosphorylation in adipocytes by protein-tyrosine phosphatase 1B
                  • Article
                  • Peer Reviewed
                  UC Davis Previously Published Works (2021)
                  Salmonella serotype (ser.) Enteritidis infection in broilers is a main foodborne illness that substantially threatens food security. This study aimed to examine the effects of a novel polysaccharide isolated from alfalfa (APS) on the intestinal microbiome and systemic health of S. ser. Enteritidis-infected broilers. The results indicated that broilers receiving the APS-supplemented diet had the improved (P < 0.05) growth performance and gut health than those fed no APS-supplemented diet. Supplementation with APS enhanced (P < 0.05) the richness of gut beneficial microbes such as Bacteroidetes, Barnesiella, Parabacteroides, Butyricimonas, and Prevotellaceae, while decreased (P < 0.05) the abundance of facultative anaerobic bacteria including Proteobacteria, Actinobacteria, Ruminococcaceae, Lachnospiraceae, and Burkholderiaceae in the S. ser. Enteritidis-infected broilers. The Bacteroides and Odoribacter were identified as the two core microbes across all treatments and combined with their syntrophic microbes formed the hub in co-occurrence networks linking microbiome structure to performance of broilers. Taken together, dietary APS supplementation improved the systemic health of broilers by reshaping the intestinal microbiome regardless of whether S. ser. Enteritidis infection was present. Therefore, APS can be employed as a potential functional additives to inhibit the S. ser. Enteritidis and enhance the food safety in poultry farming.
                    Cover page: The modulatory effects of alfalfa polysaccharide on intestinal microbiota and systemic health of Salmonella serotype (ser.) Enteritidis-challenged broilers
                    • Article
                    • Peer Reviewed
                    UC Davis Previously Published Works (2016)
                    Obesity and type 2 diabetes (T2D) are major public health concerns. Visceral adipose tissue inflammation is considered a significant contributor to obesity-associated T2D development. We previously showed that the flavan-3-ol (-)-epicatechin (EC) can mitigate insulin resistance in mice fed a high fat diet (HFD). This study investigated the capacity of EC to inhibit visceral adipose tissue inflammation occurring as a consequence of HFD consumption in C57BL/6J mice, and characterized the underlying mechanisms. In association with the development of obesity and insulin resistance, HFD consumption caused inflammation in the visceral adipose tissue as evidenced by activation of the pro-inflammatory transcription factor NF-κB and increased tissue levels of the macrophage marker F4/80, tumor necrosis factor alpha (TNFα), and the chemokine MCP-1. EC supplementation mitigated all these events. In addition, we observed activation of the three branches of the unfolded protein response (UPR), and upregulation of NADPH oxidases NOX4 and NOX2 in visceral fat of mice fed HFD. These can account, at least in part, for the associated oxidative stress and activation of the redox sensitive NF-κB. Notably, EC supplementation mitigated this and the release of pro-inflammatory proteins from metabolically stressed adipocytes. Attenuation of adipocyte endoplasmic reticulum (ER) and oxidative stress by EC could contribute to decreased inflammation and improved visceral adipose tissue insulin sensitivity. Our results support the concept that consumption of EC-rich foods could mitigate obesity-associated insulin resistance through attenuation of adipose tissue inflammation.
                      Cover page: Anti-inflammatory actions of (-)-epicatechin in the adipose tissue of obese mice.
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