Coordinated control of bile acids and lipogenesis through FXR-dependent regulation of fatty acid synthase.

We discovered a nuclear receptor element in the FAS promoter consisting of an inverted repeat spaced by one nucleotide (IR-1) and located 21 bases downstream of a direct repeat sequenced by 4 nucleotides (DR-4) oxysterol liver X receptor response element. An IR-1 is present in promoters of several genes of bile acid and lipid homeostasis and binds farnesoid X receptor/retinoid X receptor (FXR/RXR) heterodimers to mediate bile acid-dependent transcription. We show that FXR/RXRalpha specifically binds to the FAS IR-1 and that the FAS promoter is activated approximately 10-fold by the addition of a synthetic FXR agonist in transient transfection assays. We also demonstrate that endogenous FXR binds directly to the murine FAS promoter in the hepatic genome using a tissue-based chromatin immunoprecipitation procedure. Furthermore, we show that feeding wild-type mice a chow diet supplemented with the natural FXR agonist chenodeoxycholic acid results in a significant induction of FAS mRNA expression. Thus, we have identified a novel IR-1 in the FAS promoter and demonstrate that it mediates FXR/bile acid regulation of the FAS gene. These findings provide the first evidence for direct regulation of lipogenesis by bile acids and also provide a mechanistic rationale for previously unexplained observations regarding bile acid control of FAS expression.

Evidence of biochemical and biomagnetic interactions in Alzheimer's disease: an MEG and MR spectroscopy study.

BACKGROUND: Several neuroimaging studies have shown reliable differences between Alzheimer's disease (AD) patients and age-matched controls. However, few studies have demonstrated the interactions between neuroimaging methods for the diagnoses of AD. OBJECTIVE: In this study, we try to elucidate the complementary nature of magnetoencephalography (MEG) and magnetic resonance spectroscopy (MRS) examinations in the assessmentof AD. METHODS: Ten patients fulfilling the NINCDS-ADRDA criteria of probable AD, and 10 elderly individuals with no history of neurological or psychiatric illness serving as age-matched controls participated in the study. All patients and controls received an MRS, MEG and neuropsychological assessment. MEG data were obtained in the context of a working memory task, previously utilized in a similar sample of patients. RESULTS: The AD group showed a reduced number of activity sources over left temporoparietal areas during the late portion of the evoked magnetic field (between 400-800 ms), as well as a bilateral temporoparietal increase in creatine and myoinositol concentrations, and in the myoinositol/N-acetyl-aspartate ratio. The combination of the variables 'number of dipoles during the late portion of the evoked magnetic field' and 'myoinositol/N-acetyl-aspartate ratio' accounted for 65% of the variance of the Mini Mental State Examination scores. CONCLUSIONS: These results highlight the importance of assessing the complex brain pathology underlying AD by utilizing multiple brain examination modalities in a coordinate approach.

Regulation of group VIA phospholipase A2 expression by sterol availability.

Several lines of evidence suggest that glycerophospholipid mass is maintained through the coordinate regulation of CTP:phosphocholine cytidylyltransferase-alpha (CTalpha) and the group VIA calcium-independent phospholipase A2 (iPLA2). CTalpha expression is modulated by sterol and this is mediated in part through sterol regulatory element binding proteins (SREBP). In this report, we investigate the possibility that iPLA2 expression is controlled in a similar manner. When Chinese hamster ovary (CHO) cells were cultured under sterol-depleted conditions, iPLA2 catalytic activity, mRNA, and protein were induced by between two- and threefold. These inductions were suppressed when the cells were supplemented with exogenous sterols. Luciferase reporter assays indicated that sterol depletion induced transcription of iPLA2, an analysis of the 5' flanking region suggested that the iPLA2 gene contained a putative sterol regulatory element (SRE), and electrophoretic mobility shift assay (EMSA) analysis indicated that this element can bind SREBP-2. Notably, a mutant CHO cell line (SRD4) that constitutively generates mature SREBP proteins exhibited increased iPLA2 activity and expression compared to wild-type cells. These data suggest that iPLA2 expression is regulated in a manner consistent with other important genes in sterol and glycerophospholipid metabolism. Such coordinate regulation may be essential for maintaining the lipid composition of cell membranes.

Dementia and Nutrition. Intervention study in institutionalized patients with Alzheimer disease.

OBJECTIVES: To know nutritional status of a group of institutionalized patients with moderate Alzheimer's Disease (AD), and to ascertain the effects of an intervention with nutritional supplements on morbidity and mortality after one year follow-up. PATIENTS AND METHODS: 99 patients (mean age: 86.5 years), 80 women, with a diagnosis of AD according with NINCDS/ADRDA criteria, were recruited from 8 nursing-homes. 25 were included in an intervention group and received a nutritional supplements along 12 months. Evolution was evaluated according to the Functional Assessment Staging Test (FAST). Patients with FAST levels 5-6 were included. General clinical variables as well as variables reflecting cognitive state and nutritional status: anthropometric, biochemical data and Mini Nutritional Assessment (MNA) were analysed. Statistical analysis was carry out with the SPSS 10.0 package. RESULTS: Mean time since diagnosis was 49 months, with a 20.2 months duration of institutionalization. Mean value of MNA was 20.1 3.5. 16.5% of patients had a BMI equal o lower than 21. After one year the intervention group showed higher levels of albumin (P=05), pre-albumin (P=05), iron (P=01), zinc (P=05), and beta-carotene (P=05) than the control group. The same response in BMI (P=05), MNA (P=05), and triceps skinfold (P=01). Mortality was lower (16% vs. 22.7%), without statistical significance, in the intervention group, as it was the number of infectious events (47% vs. 66% P=05), and the days in bed (7.5 2.1 vs. 17.3 5.6 P=05). CONCLUSION: Nutritional supplements applied to a group of patients with AD living in nursing-homes can reduce morbidity and mortality after one year follow-up.