Large but not small cholangiocytes: (i) secrete bicarbonate by interaction with secretin receptors (SR) through activation of cystic fibrosis transmembrane regulator (CFTR), chloride bicarbonate anion exchanger 2 (Cl−/HCO3− AE2) and adenylyl cyclase 8 (AC8) (proteins regulating large biliary functions); and (ii) proliferate in response to bile duct ligation (BDL) by activation of cAMP signaling. Small, mitotically dormant cholangiocytes are activated during damage of large cholangiocytes by activation of IP3/Ca2+-CaMK I. GABA affects cell functions by modulation of Ca2+-dependent signaling and AC. We hypothesized that GABA induces the differentiation of small into large cholangiocytes by the activation of Ca2+/CaMK I-dependent AC 8. Methods In vivo, BDL mice were treated with GABA in the absence/presence of BAPTA/AM or W7 before evaluating apoptosis and ductal mass (IBDM) of small and large cholangiocytes. In vitro, control- or CaMK I-silenced small cholangiocytes were treated with GABA for 3 days before evaluating apoptosis, proliferation, ultrastructural features and the expression of CFTR, Cl−/HCO3− AE2 and AC8, and secretin-stimulated cAMP levels. Results In vivo administration of GABA induces the apoptosis of large but not small cholangiocytes, and decreases large IBDM but increased de novo small IBDM. GABA-stimulation of small IBDM was blocked by BAPTA/AM and W7. Following GABA in vitro treatment, small cholangiocytes de novo proliferate and acquire ultrastructural and functional phenotypes of large cholangiocytes and respond to secretin. GABA-induced changes were prevented by BAPTA/AM, W7 and by stable knockdown of CaMK I gene. Conclusion GABA damages large but not small cholangiocytes that differentiate into large cholangiocytes. The differentiation of small into large cholangiocytes may be important in the replenishment of the biliary epithelium during damage of large, senescent cholangiocytes.
Background The evidence associating diet and risk of multiple sclerosis (MS) is inconclusive. Objectives The aim of this study was to investigate associations between a Mediterranean diet and risk of a first clinical diagnosis of central nervous system demyelination (FCD), a common precursor to MS. Methods We used data from the 2003–2006 Ausimmune Study, an Australian multicenter, case-control study examining environmental risk factors for FCD, with participants matched on age, sex, and study region (282 cases, 558 controls; 18–59 y old; 78% female). The alternate Mediterranean diet score (aMED) was calculated based on data from a food-frequency questionnaire. We created a modified version of the aMED (aMED-Red) where ∼1 daily serving (65 g) of unprocessed red meat received 1 point. All other components remained the same as aMED. Conditional logistic regression (254 cases, 451 controls) was used to test associations between aMED and aMED-Red scores and categories and risk of FCD, adjusting for history of infectious mononucleosis, serum 25-hydroxyvitamin D concentrations, smoking, education, total energy intake, and dietary underreporting. Results There was no statistically significant association between aMED and risk of FCD [per 1-SD increase in aMED score: adjusted odds ratio (aOR): 0.89; 95% CI: 0.75, 1.06; P = 0.181]. There was evidence of a nonlinear relation between aMED-Red and risk of FCD when a quadratic term was used (P = 0.016). Compared with the lowest category of aMED-Red, higher categories were significantly associated with reduced risk of FCD, corresponding to a 37% (aOR: 0.63; 95% CI: 0.41, 0.98; P = 0.039), 52% (aOR: 0.48; 95% CI: 0.28, 0.83; P = 0.009), and 42% (aOR: 0.58; 95% CI: 0.35, 0.96; P = 0.034) reduced risk of FCD in categories 2, 3, and 4, respectively. Conclusions A Mediterranean diet, including unprocessed red meat, was associated with reduced risk of FCD in this Australian adult population. The addition of unprocessed red meat to a Mediterranean diet may be beneficial for those at high risk of MS.
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