Gender and gut microbiota composition determine hepatic bile acid, metabolic and inflammatory response to a single fast-food meal in healthy adults.

BACKGROUND & AIMS: Regular consumption of fast-food (FF) as a form of typical Western style diet is associated with obesity and the metabolic syndrome, including its hepatic manifestation nonalcoholic fatty liver disease. Currently, it remains unclear how intermittent excess FF consumption may influence liver metabolism. The study aimed to characterize the effects of a single FF binge on hepatic steatosis, inflammation, bile acid (BA), glucose and lipid metabolism. METHODS: Twenty-five healthy individuals received a FF meal and were asked to continue eating either for a two-hour period or until fully saturated. Serum levels of transaminases, fasting BA, lipid profile, glucose and cytokine levels as well as transient elastography and controlled attenuation parameter (CAP; to assess hepatic steatosis) were analyzed before (day 0) and the day after FF binge (day 1). Feces was collected prior and after the FF challenge for microbiota analysis. RESULTS: The FF meal induced a modest increase in CAP, which was accompanied by a robust increase of fasting serum BA levels. Surprisingly, levels of cholesterol and bilirubin were significantly lower after the FF meal. Differentiating individuals with a relevant delta BA (>1 µmol/l) increase vs. individuals without (delta BA ≤1 µmol/l), identified several gut microbiota, as well as gender to be associated with the BA increase and the observed alterations in liver function, metabolism and inflammation. CONCLUSION: A single binge FF meal leads to a robust increase in serum BA levels and alterations in parameters of liver injury and metabolism, indicating a novel metabolic aspect of the gut-liver axis.

[Molecular genetics of cholesterol cholelithiasis: identification of human and murine gallstone genes]. / Molekulargenetik der Cholesterin-Cholelithiasis: Identifizierung humaner und muriner Gallensteingene.

Cholesterol cholelithiasis is one of the most common gastroenterological diseases in Western countries. It is a polygenic disease resulting from disturbed biliary cholesterol homeostasis. Association studies identified six human gallstone candidate genes. Polymorphisms in the genes encoding the apolipoproteins B and E, phospholipid flippase ( ABCB4), cholesterol ester transfer protein ( CETP), cholesterol-7alpha-hydroxylase ( CYP7A1) and ileal bile acid transporter ( SLC10A2) are correlated with gallstone prevalence. Quantitative Trait Locus (QTL) analysis localises additional unknown gallstone genes in inbred mice. Based on the natural variation of cholesterol gallstone susceptibility among different inbred strains, 5 lithogenic ( Lith) loci have been identified. Hepatobiliary transporters (e. g. bile salt export pump Abcb11) and key proteins of the lipoprotein metabolism (e. g. hepatic lipase Lipc) could be established as creedal candidate genes for Lith loci. The rapid progress of mouse and human genome projects provides the basis for the analysis of orthologous human LITH genes in gallstone patients, which might offer new prospects for individual risk assessment and molecular targets for stone prevention.

Interaction of serotonin 5-hydroxytryptamine type 2C receptors with PDZ10 of the multi-PDZ domain protein MUPP1.

By using the yeast two-hybrid system, we previously isolated a cDNA clone encoding a novel member of the multivalent PDZ protein family called MUPP1 containing 13 PDZ domains. Here we report that the C terminus of the 5-hydroxytryptamine type 2C (5-HT(2C)) receptor selectively interacts with the 10th PDZ domain of MUPP1. Mutations in the extreme C-terminal SSV sequence of the 5-HT(2C) receptor confirmed that the SXV motif is critical for the interaction. Co-immunoprecipitations of MUPP1 and 5-HT(2C) receptors from transfected COS-7 cells and from rat choroid plexus verified this interaction in vivo. Immunocytochemistry revealed an SXV motif-dependent co-clustering of both proteins in transfected COS-7 cells as well as a colocalization in rat choroid plexus. A 5-HT(2C) receptor-dependent unmasking of a C-terminal vesicular stomatitis virus epitope of MUPP1 suggests that the interaction triggers a conformational change within the MUPP1 protein. Moreover, 5-HT(2A) and 5-HT(2B), sharing the C-terminal EX(V/I)SXV sequence with 5-HT(2C) receptors, also bind MUPP1 PDZ domains in vitro. The highest MUPP1 mRNA levels were found in all cerebral cortical layers, the hippocampus, the granular layer of the dentate gyrus, as well as the choroid plexus, where 5-HT(2C) receptors are highly enriched. We propose that MUPP1 may serve as a multivalent scaffold protein that selectively assembles and targets signaling complexes.

Cloning and characterization of MUPP1, a novel PDZ domain protein.

Using the yeast two-hybrid system we isolated a cDNA clone encoding a novel protein interacting with the C-terminal domain of the 5-HT2C receptor. The protein, named MUPP1 (multi-PDZ-domain protein), contains thirteen PDZ domains and no obvious catalytic domain; it is related to hINADL and a putative C. elegans polypeptide referred to as C52A11.4 containing six or ten PDZ domains, respectively. Domains highly similar to those of MUPP1 are arrayed in the same order in all three proteins. The MUPP1 gene is localized on human chromosome 9p24-p22. Transcripts encoding MUPP1 are abundant in the brain as well as in several peripheral organs.

Correlation of germ-line mutations and two-hit inactivation of the WT1 gene with Wilms tumors of stromal-predominant histology.

The WT1 gene, located on chromosome 11p13, is mutated in a low number of Wilms tumors (WTs). Germ-line mutations in the WT1 gene are found in patients with bilateral WT and/or associated genital tract malformations (GU). We have identified 19 hemizygous WT1 gene mutations/deletions in 64 patient samples. The histology of the tumors with mutations was stromal-predominant in 13, triphasic in 3, blastemal-predominant in 1, and unknown in 2 cases. Thirteen of 21 patients with stromal-predominant tumors had WT1 mutations and 10 of these were present in the germ line. Of the patients with germ-line alterations, six had GU and a unilateral tumor, two had a bilateral tumor and normal GU tracts, and two had a unilateral tumor and normal GU. Three mutations were tumor-specific and were found in patients with unilateral tumors without GU. These data demonstrate a correlation of WT1 mutations with stromal-predominant histology, suggesting that a germ-line mutation in WT1 predisposes to the development of tumors with this histology. Twelve mutations are nonsense mutations resulting in truncations at different positions in the WT1 protein and only two are missense mutations. Of the stromal-predominant tumors, 67% showed loss of heterozygosity, and in one tumor a different somatic mutation in addition to the germ-line mutation was identified. These data show that in a large proportion of a histopathologically distinct subset of WTs the classical two-hit inactivation model, with loss of a functional WT1 protein, is the underlying cause of tumor development.

[Patulin in foods of vegetable origin. 2. Several kinds of fruit and vegetables and fruit and vegetable products (author's transl)]. / Patulin in Lebensmitteln pflanzlicher Herkunft. 2. Verschiedene Obstarten, Gemüse und daraus hergestellte Produkte

Patulin was found in fruit with spontaneous brown rot (bananas, pineapples, grapes, peaches, apricots) as well as in moldy compots and in sallow-thorn juice. Fruit, vegetables and fruit and vegetable product were artificially infected with Penicillium expansum, P. urticae and Byssochlamys nivea; patulin was subsequently found in peaches, apricots, greengages, bananas, strawberries, honeydew melons, tomatoes, red and green paprika, cucumbers and carrots; in several kinds of compot, in tomato juice and tomato pulp --but not in ketchup. The influence of the temperature on growth and toxin production is different in the various fungal strains; in the temperature range of 5 degrees C to 25 degrees C, however, the possibility of patulin synthesis must nearly always be expected.