No abstract

Highlights d Upon demyelination, Trem2 -/microglia fail to upregulate lipid metabolism genes d Trem2 -/microglia accumulate cholesteryl ester derived from myelin cholesterol d Accumulation is rescued by ACAT1 inhibitor and LXR agonist d Apoe -/glia defective in cholesterol transport also accumulate cholesteryl ester

Nonalcoholic fatty liver disease (NAFLD) covers a spectrum of liver damage ranging from simple steatosis to nonalcoholic steatohepatitis (NASH), fibrosis, and cirrhosis. To date, no pharmacological treatment is approved for NAFLD/NASH. Here, we report on preclinical and clinical data with GFT505, a novel dual peroxisome proliferator‐activated receptor alpha/delta (PPAR‐α/δ) agonist. In the rat, GFT505 concentrated in the liver with limited extrahepatic exposure and underwent extensive enterohepatic cycling. The efficacy of GFT505 was assessed in animal models of NAFLD/NASH and liver fibrosis (Western diet [WD]‐fed human apolipoprotein E2 [hApoE2] transgenic mice, methionine‐ and choline‐deficient diet‐fed db/db mice, and CCl4‐induced fibrosis in rats). GFT505 demonstrated liver‐protective effects on steatosis, inflammation, and fibrosis. In addition, GFT505 improved liver dysfunction markers, decreased hepatic lipid accumulation, and inhibited proinflammatory (interleukin‐1 beta, tumor necrosis factor alpha, and F4/80) and profibrotic (transforming growth factor beta, tissue inhibitor of metalloproteinase 2, collagen type I, alpha 1, and collagen type I, alpha 2) gene expression. To determine the role of PPAR‐α‐independent mechanisms, the effect of GFT505 was assessed in hApoE2 knock‐in/PPAR‐α knockout mice. In these mice, GFT505 also prevented WD‐induced liver steatosis and inflammation, indicating a contribution of PPAR‐α‐independent mechanisms. Finally, the effect of GFT505 on liver dysfunction markers was assessed in a combined analysis of four phase II clinical studies in metabolic syndrome patients. GFT505 treatment decreased plasma concentrations of alanine aminotransferase, gamma‐glutamyl transpeptidase, and alkaline phosphatase. Conclusion: The dual PPAR‐α/δ agonist, GFT505, is a promising liver‐targeted drug for treatment of NAFLD/NASH. In animals, its protective effects are mediated by both PPAR‐α‐dependent and ‐independent mechanisms. (Hepatology 2013; 58:1941–1952)

No abstract

-To assess the relationship between conditions of milk production and cheese contents of components of nutritional interest, it is necessary to know to what extent the compositional variability of cheese depends on that of milk. The respective effects of milk composition and the cheese-making process on cheese compositional variability in components of nutritional interest were therefore studied under real conditions of cheese production considering four different cheese-making technologies. The nutritional characteristics of the original milk were subject to high variations partly due to animal species (cow vs. goat). Apart from the aspects related to the dry matter content of cheese, the cheese compositional variability in fatty acids, β-carotene, xanthophylls and vitamin E depended mainly on the composition of the original milk. For vitamin A, it was partially influenced by both the original milk composition and the cheese-making process. Regarding folates and minerals, as well as total antioxidant capacity, the cheese composition varied mainly with the cheese-making process. In addition, the cheese-making technology had a significant effect on the cheese composition in minerals and folates, but did not influence the other components affected by the cheesemaking process. Consequently, the cheese contents of fat-soluble compounds depend directly on the conditions of milk production. On the contrary, the composition of cheese in water-soluble compounds varies independently of the conditions of milk production. The total antioxidant capacity of pressed cheeses, unlike the original milk, was positively correlated with some fat-soluble antioxidants. It could therefore be influenced by the conditions of milk production. Résumé -Effets respectifs de la composition du lait et de la transformation fromagère sur la variabilité de composition du fromage en composés d'intérêt nutritionnel. De façon à étudier la relation entre les conditions de production du lait et les teneurs en composés d'intérêt nutritionnel dans le fromage, il est nécessaire de savoir dans quelle mesure la variabilité de composition du fromage dépend de celle du lait d'origine. Les effets respectifs de la composition du lait et de la transformation fromagère sur la variabilité de composition du fromage en composés d'intérêt nutritionnel ont donc été étudiés en conditions réelles de production du fromage et en considérant quatre technologies fromagères différentes. Les caractéristiques nutritionnelles du lait à l'origine du fromage sont soumises à de grandes variations en partie dues à l'espèce animale (vache vs. chèvre). Mis à part les aspects liés à la teneur en matière sèche du fromage, la variabilité de composition du fromage en acides gras, en β-carotène, en xanthophylles et en vitamine E dépend principalement de la composition du lait d'origine, alors que pour la vitamine A celle-ci est influencée à la fois par la composition du lait d'origine et par la transformation fromagère. Par contre, la composition en folates et en minéraux du fr...

The nuclear bile acid receptor farnesoid X receptor (FXR) is an important transcriptional regulator of bile acid, lipid, and glucose metabolism. FXR is highly expressed in the liver and intestine and controls the synthesis and enterohepatic circulation of bile acids. However, little is known about FXR-associated proteins that contribute to metabolic regulation. Here, we performed a mass spectrometry-based search for FXR-interacting proteins in human hepatoma cells and identified AMPK as a coregulator of FXR. FXR interacted with the nutrient-sensitive kinase AMPK in the cytoplasm of target cells and was phosphorylated in its hinge domain. In cultured human and murine hepatocytes and enterocytes, pharmacological activation of AMPK inhibited FXR transcriptional activity and prevented FXR coactivator recruitment to promoters of FXR-regulated genes. Furthermore, treatment with AMPK activators, including the antidiabetic biguanide metformin, inhibited FXR agonist induction of FXR target genes in mouse liver and intestine. In a mouse model of intrahepatic cholestasis, metformin treatment induced FXR phosphorylation, perturbed bile acid homeostasis, and worsened liver injury. Together, our data indicate that AMPK directly phosphorylates and regulates FXR transcriptional activity to precipitate liver injury under conditions favoring cholestasis.

The oral administration of lanthanum carbonate to normal rats leads to a more than 10-fold increase of tissue La content in at least some organs, including the liver, lung, and kidney. This increase is further enhanced by the uremic state, per se. Plasma levels are a poor indicator of tissue burden. Given the dramatic tissue levels obtained with this rare earth metal given by the oral route, particularly in liver for absolute values, it is probable that the stimulation by CRF is at least partially explained by an increase in intestinal La absorption. The absorptive pathways involved in intestinal La absorption require further study, including possibly enhancing conditions.

Visible-near-infrared reflectance spectroscopy was used to predict dry matter, fat, pH, retinol, alpha-tocopherol, beta-carotene, xanthophylls, sodium chloride, calcium, potassium, magnesium, zinc, total antioxidant capacity, brightness, redness, and yellowness in both fresh and freeze-dried cheeses. A total of 445 cheeses of four cheese varieties were investigated. Composition of samples was analyzed by reference methods. Samples were scanned (400-2500 nm) and predictive equations were developed using modified partial least-squares with both cross-validation and external validation. Coefficient of determination (R(2)) and residual predictive deviation (RPD) in external validation were satisfactory for dry matter (0.97; 5.99), fat (0.90; 3.22), beta-carotene (0.92; 3.43), sodium chloride (0.89; 2.94), calcium (0.95; 4.62), Zinc (0.93; 3.75), brightness (0.96; 4.88), redness (0.96; 5.23), and yellowness (0.93; 3.73) in fresh cheeses. Poor predictions were obtained for pH, retinol, alpha-tocopherol, xanthophylls, potassium, magnesium, and total antioxidant capacity (R(2) < 0.81; RPD < 3).