BILE ACID SIGNALING AND THE REGULATION OF THE COMPLEMENT COMPONENT C3 ALTERNATIVE ACTIVATION PATHWAY PROTEINS
Open Access
- Author:
- Noel, Olivier Francois
- Graduate Program:
- Biomedical Sciences
- Degree:
- Doctor of Philosophy
- Document Type:
- Dissertation
- Date of Defense:
- December 14, 2017
- Committee Members:
- James Riley Broach, Dissertation Advisor/Co-Advisor
James Riley Broach, Committee Chair/Co-Chair
Keith C Cheng, Committee Member
Charles H Lang, Committee Member
Diane M Thiboutot, Outside Member
Glenn S Gerhard, Special Member - Keywords:
- Bile acids
FXR
RYGB
Bariatric surgery
Complement pathway
Complement C3 Alternative pathway
Diabetes Mellitus
C5L2
ASP - Abstract:
- Over 6% of the US population [1] are considered to be extremely obese (BMI>40 kg/m2) with a prevalence of Type 2 Diabetes (T2D) of over 30% [2]. Treatments for extreme obesity include certain types of bariatric surgery, e.g., Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG), that can result in long-term remission of T2D [3]. These interventions also induce a dramatic reduction in fasting plasma glucose within hours to days of the procedure, well before weight loss and a variety of other complex metabolic effects have occurred [1]. Although few studies have focused on the initial favorable weight loss-independent effects, a number of theories for the improvements in dysglycemia have been proposed [4]. Our published [5] and preliminary data, and those of others [6] , as well as a recent systematic review [7], support a mechanistic role for bile acids [8]. Bile acid levels and/or metabolism are altered by RYGB and SG consistent with ileal interposition and surgical diversion of the bile duct to the distal intestine that can also induce weight loss-independent amelioration of dysglycemia in rodent models [4]. Bile acids serve as ligands for the G-protein coupled receptor GPBAR1 (TGR5) [9] and the farnesoid X receptor (FXR) nuclear transcription factor [10]. Recent work in obese rodent models of bariatric surgery indicates that FXR appears to be required for both weight loss and normalization of dysglycemia [11], and that TGR5 modulates dysglycemia through effects on the bile acid pool [12], further implicating FXR. The specific molecular mediators that operate downstream from bile acids and FXR have not yet been identified. Using an unbiased proteomics approach, we identified changes in complement component C3 (C3) occurring within 2 days after RYGB. C3’s proteolytic derivative, C3adesArg, also known as acylation stimulating protein (ASP), correspondingly increased. C3 is produced primarily by adipocytes, is regulated by FXR [13], and is part of the immunological response in obesity that can induce insulin resistance and contribute to the development of T2D [14]. ASP has been shown to mediate fatty acid and glucose transport as part of an anabolic pathway for triglyceride synthesis [15, 16]. We identified FXR consensus sequence motifs in the Complement Factor B (CFB), Complement Factor D (Adipsin or CFD), and carboxypeptidase B (CPB) genes, the complement alternative activation pathway components that generate ASP from C3, as well as in the C5a like-2 receptor (C5AR2 or C5L2) gene, which serves as a receptor for ASP. Targeted disruption of C5L2 in mice enhances the development of diet-induced insulin resistance in mice [15] further implicating the C3 alternative activation pathway in promoting glucose uptake. ASP mediates glucose transport in adipocytes through enhanced translocation of glucose transporters to the plasma membrane surface that has been reported to be insulin-independent [17]. The signaling pathway has not been defined and the effects of bile acids have not been determined. The presence of FXR sequence motifs in several genes encoding members of the C3 complement alternative activation pathway suggest regulation by bile acids, as has been reported for C3 [18] . We determined the functionality of FXR sites in C3 complement alternative activation pathway downstream receptor protein C5L2 and provided initial insight into its gene regulation. We also showed that bile acids could act as a potentiator for the effects of insulin in vitro, ultimately leading to an increase in glucose transport into cells. This observation is consistent the immediate glucose normalization occurring in a number of patients following bariatric surgery. The identification of a novel glucose metabolic pathway synergistic with insulin uncovered by the intervention of bariatric surgery that is regulated by bile acids may have important implications for the treatment of T2D. Further delineation of the molecular mechanisms underlying the beneficial effects of this pathway could provide targets for the development of new non-surgical treatments [19].