Foxa1 Reduces Lipid Accumulation in Human Hepatocytes and Is Down-Regulated in Nonalcoholic Fatty Liver

Triglyceride accumulation in nonalcoholic fatty liver (NAFL) results from unbalanced lipid metabolism which, in the liver, is controlled by several transcription factors. The Foxa subfamily of winged helix/forkhead box (Fox) transcription factors comprises three members which play important roles in controlling both metabolism and homeostasis through the regulation of multiple target genes in the liver, pancreas and adipose tissue. In the mouse liver, Foxa2 is repressed by insulin and mediates fasting responses. Unlike Foxa2 however, the role of Foxa1 in the liver has not yet been investigated in detail. In this study, we evaluate the role of Foxa1 in two human liver cell models, primary cultured hepatocytes and HepG2 cells, by adenoviral infection. Moreover, human and rat livers were analyzed to determine Foxa1 regulation in NAFL. Results demonstrate that Foxa1 is a potent inhibitor of hepatic triglyceride synthesis, accumulation and secretion by repressing the expression of multiple target genes of these pathways (e.g., GPAM, DGAT2, MTP, APOB). Moreover, Foxa1 represses the fatty acid transporter protein FATP2 and lowers fatty acid uptake. Foxa1 also increases the breakdown of fatty acids by inducing peroxisomal fatty acid β-oxidation and ketone body synthesis. Finally, Foxa1 is able to largely up-regulate UCP1, thereby dissipating energy and consistently decreasing the mitochondria membrane potential. We also report that human and rat NAFL have a reduced Foxa1 expression, possibly through a protein kinase C-dependent pathway. We conclude that Foxa1 is an antisteatotic factor that coordinately tunes several lipid metabolic pathways to block triglyceride accumulation in hepatocytes. However, Foxa1 is down-regulated in human and rat NAFL and, therefore, increasing Foxa1 levels could protect from steatosis. Altogether, we suggest that Foxa1 could be a novel therapeutic target for NAFL disease and insulin resistance

Are women better mindreaders? Sex differences in neural correlates of mentalizing detected with functional MRI

<p>Abstract</p> <p>Background</p> <p>The ability to mentalize, i.e. develop a Theory of Mind (ToM), enables us to anticipate and build a model of the thoughts, emotions and intentions of others. It has long been hypothesised that women differ from men in their mentalizing abilities. In the present fMRI study we examined the impact of (1) gender (women vs. men) and (2) game partner (human vs. computer) on ToM associated neural activity in the medial prefrontal cortex. Groups of men (n = 12) and women (n = 12) interacted in an iterated classical prisoner's dilemma forced choice situation with alleged human and computer partners who were outside the scanner.</p> <p>Results</p> <p>Both the conditions of playing against putative human as well as computer partners led to activity increases in mPFC, ACC and rTPJ, constituting the classic ToM network. However, mPFC/ACC activity was more pronounced when participants believed they were playing against the alleged human partner. Differences in the medial frontal lobe activation related to the sex of the participants could be demonstrated for the human partner > computer partner contrast.</p> <p>Conclusion</p> <p>Our data demonstrate differences in medial prefrontal brain activation during a ToM task depending on both the gender of participants and the game partner.</p