http://repub.eur.nl/res/aut/55664/ List of Publications en http://repub.eur.nl/static-eur/img/logo.png http://repub.eur.nl http://repub.eur.nl/res/pub/37407/ 2012-10-01T00:00:00Z Background: Nonalcoholic fatty liver disease is closely associated with metabolic syndrome and cardiovascular disease (CVD). We investigated whether the liver fat content (LFC) is independently associated with carotid artery intima-media thickness (CIMT) and evaluated the contribution of the LFC to the increased CIMT. Methods: We conducted a community-based study among 1809 participants (682 males and 1127 females) from the Changfeng Study who were at least 45 years old. A standard interview, anthropometrics and laboratory parameters were performed for each participant. The CIMT was determined by ultrasonography. A large CIMT value was defined as 75th percentile of the maximum CIMT. A standardised ultrasonographic hepatic-renal ratio was used to assess the LFC. Results: The median LFC value was 6% (interquartile range, 3-14%), and 34% of the subjects had hepatic steatosis based on the criteria for diagnosis of steatosis by quantitative ultrasound. The maximum CIMT, average CIMT and plaque score were strongly associated with the LFC (β = 0.319, 0.324 and 1.361, respectively; all P < 0.05) after adjustment for age, gender, smoking history, low-density lipoprotein cholesterol and metabolic syndrome. The multiple logistic regression analysis showed that a 1 SD increase in the LFC, the OR for having a large CIMT was 1.350 (95% CI 1.180-1.545; P < 0.001) after adjustment for all potential confounders. Conclusions: These results suggest that the LFC is independently associated with carotid atherosclerosis in the Chinese population, and that the risk of atherosclerosis is proportional to the degree of hepatic steatosis. http://repub.eur.nl/res/pub/35251/ 2007-08-24T00:00:00Z The multi-PDZ domain containing protein Na+/H+Exchanger Regulatory Factor 1 (NHERF1) binds to Na+/H+exchanger 3 (NHE3) and is associated with the brush border (BB) membrane of murine kidney and small intestine. Although studies in BB isolated from kidney cortex of wild type and NHERF1-/-mice have shown that NHERF1 is necessary for cAMP inhibition of NHE3 activity, a role of NHERF1 in NHE3 regulation in small intestine and in intact kidney has not been established. Here a method using multi-photon microscopy with the pH-sensitive dye SNARF-4F (carboxyse-minaphthorhodafluors-4F) to measure BB NHE3 activity in intact murine tissue and use it to examine the role of NHERF1 in regulation of NHE3 activity. NHE3 activity in wild type and NHERF1-/-ileum and wild type kidney cortex were inhibited by cAMP, whereas the cAMP effect was abolished in kidney cortex of NHERF1-/-mice. cAMP inhibition of NHE3 activity in these two tissues is mediated by different mechanisms. In ileum, a protein kinase A (PKA)-dependent mechanism accounts for all cAMP inhibition of NHE3 activity since the PKA antagonist H-89 abolished the inhibitory effect of cAMP. In kidney, both PKA-dependent and non-PKA-dependent mechanisms were involved, with the latter reproduced by the effect on an EPAC (exchange protein directly activated by cAMP) agonist (8-(4-chlorophenylthio)-2′O-Me-cAMP). In contrast, the EPAC agonist had no effect in proximal tubules in NHERF1-/-mice. These data suggest that in proximal tubule, NHERF1 is required for all cAMP inhibition of NHE3, which occurs through both EPAC-dependent and PKA-dependent mechanisms; in contrast, cAMP inhibits ileal NHE3 only by a PKA-dependent pathway, which is independent of NHERF1 and EPAC.