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postgraduate thesis: Functional characterisation of a novel kinase, SH3 domain binding kinase 1 (SBK1), in glucose homeostasis
Title | Functional characterisation of a novel kinase, SH3 domain binding kinase 1 (SBK1), in glucose homeostasis |
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Authors | |
Advisors | |
Issue Date | 2020 |
Publisher | The University of Hong Kong (Pokfulam, Hong Kong) |
Citation | Ahuja, P.. (2020). Functional characterisation of a novel kinase, SH3 domain binding kinase 1 (SBK1), in glucose homeostasis. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR. |
Abstract | Type 2 diabetes mellitus (T2DM) is a major global public health concern, and its prevalence is expected to rise exponentially in the coming decades. Excess lipid accumulation in obese subjects is the major risk factor for the progression of T2DM. The current treatment strategies for diabetic patients include the restoration of insulin response by potentiating insulin signaling transduction or insulin replacement therapy. While these pharmacological interventions improve insulin sensitivity, the presence of side-effects, and low target specificity limits their therapeutic potential. Therefore, the identification of novel cellular pathways that control glucose and lipid metabolism is necessary to design better strategies for T2DM management. This study aims to identify and characterize unexplored protein(s) that potentially regulate energy homeostasis and T2DM progression. In this quest of finding novel signaling molecules, we conducted a comprehensive analysis of differentially regulated genes in diet-induced obese mice and found a novel protein kinase, SH3-domain binding kinase 1 (SBK1), to be significantly upregulated in the liver. We postulated that hepatic SBK1 might participate in the regulation of glucose and lipid metabolism. To gain further insight into SBK1’s role in the development of obesity-associated T2DM, we generated liver-specific SBK1 knockout (LSKO) mice. The metabolic outcomes of SBK1 ablation were scrutinized in mice subjected to nutrient stress. Furthermore, the underlying molecular mechanisms on how SBK1 mediates energy and glucose homeostasis were investigated using both in vitro and in vivo analysis. We found in this project that (1) SBK1 expression in the liver is elevated in mice after high-fat-diet (HFD) feeding and fasting; (2) deletion of hepatic SBK1 in mice resulted in the development of insulin resistance, which was accompanied by ectopic lipid accumulation, hyperglycemia, and glucose intolerance; (3) diminished expression and secretion of fibroblast growth factor 21 (FGF21) in mice was proposed as the causal factor for reduced insulin sensitivity in LSKO mice; and (4) mechanistically, SBK1-mediated phosphorylation of nuclear receptor subfamily 4 group A member 1 (NR4A1 or Nur77) was the key to enhance circulatory FGF21 levels. These findings suggest that hepatic SBK1 plays a key role in controlling glucose metabolism by stimulating FGF21 expression via Nur77 phosphorylation. |
Degree | Doctor of Philosophy |
Subject | Protein kinases Diabetes |
Dept/Program | Biological Sciences |
Persistent Identifier | http://hdl.handle.net/10722/310004 |
DC Field | Value | Language |
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dc.contributor.advisor | Chan, CB | - |
dc.contributor.advisor | Chow, BKC | - |
dc.contributor.author | Ahuja, Palak | - |
dc.date.accessioned | 2022-01-20T07:00:25Z | - |
dc.date.available | 2022-01-20T07:00:25Z | - |
dc.date.issued | 2020 | - |
dc.identifier.citation | Ahuja, P.. (2020). Functional characterisation of a novel kinase, SH3 domain binding kinase 1 (SBK1), in glucose homeostasis. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR. | - |
dc.identifier.uri | http://hdl.handle.net/10722/310004 | - |
dc.description.abstract | Type 2 diabetes mellitus (T2DM) is a major global public health concern, and its prevalence is expected to rise exponentially in the coming decades. Excess lipid accumulation in obese subjects is the major risk factor for the progression of T2DM. The current treatment strategies for diabetic patients include the restoration of insulin response by potentiating insulin signaling transduction or insulin replacement therapy. While these pharmacological interventions improve insulin sensitivity, the presence of side-effects, and low target specificity limits their therapeutic potential. Therefore, the identification of novel cellular pathways that control glucose and lipid metabolism is necessary to design better strategies for T2DM management. This study aims to identify and characterize unexplored protein(s) that potentially regulate energy homeostasis and T2DM progression. In this quest of finding novel signaling molecules, we conducted a comprehensive analysis of differentially regulated genes in diet-induced obese mice and found a novel protein kinase, SH3-domain binding kinase 1 (SBK1), to be significantly upregulated in the liver. We postulated that hepatic SBK1 might participate in the regulation of glucose and lipid metabolism. To gain further insight into SBK1’s role in the development of obesity-associated T2DM, we generated liver-specific SBK1 knockout (LSKO) mice. The metabolic outcomes of SBK1 ablation were scrutinized in mice subjected to nutrient stress. Furthermore, the underlying molecular mechanisms on how SBK1 mediates energy and glucose homeostasis were investigated using both in vitro and in vivo analysis. We found in this project that (1) SBK1 expression in the liver is elevated in mice after high-fat-diet (HFD) feeding and fasting; (2) deletion of hepatic SBK1 in mice resulted in the development of insulin resistance, which was accompanied by ectopic lipid accumulation, hyperglycemia, and glucose intolerance; (3) diminished expression and secretion of fibroblast growth factor 21 (FGF21) in mice was proposed as the causal factor for reduced insulin sensitivity in LSKO mice; and (4) mechanistically, SBK1-mediated phosphorylation of nuclear receptor subfamily 4 group A member 1 (NR4A1 or Nur77) was the key to enhance circulatory FGF21 levels. These findings suggest that hepatic SBK1 plays a key role in controlling glucose metabolism by stimulating FGF21 expression via Nur77 phosphorylation. | - |
dc.language | eng | - |
dc.publisher | The University of Hong Kong (Pokfulam, Hong Kong) | - |
dc.relation.ispartof | HKU Theses Online (HKUTO) | - |
dc.rights | The author retains all proprietary rights, (such as patent rights) and the right to use in future works. | - |
dc.rights | This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. | - |
dc.subject.lcsh | Protein kinases | - |
dc.subject.lcsh | Diabetes | - |
dc.title | Functional characterisation of a novel kinase, SH3 domain binding kinase 1 (SBK1), in glucose homeostasis | - |
dc.type | PG_Thesis | - |
dc.description.thesisname | Doctor of Philosophy | - |
dc.description.thesislevel | Doctoral | - |
dc.description.thesisdiscipline | Biological Sciences | - |
dc.description.nature | published_or_final_version | - |
dc.date.hkucongregation | 2021 | - |
dc.identifier.mmsid | 991044351384103414 | - |