Pu-erh tea displays cholesterol-lowering properties, but the underlying mechanism has not been elucidated. Theabrownin is one of the most active and abundant pigments in Pu-erh tea. Here, we show that theabrownin alters the gut microbiota in mice and humans, predominantly suppressing microbes associated with bile-salt hydrolase (BSH) activity. Theabrownin increases the levels of ileal conjugated bile acids (BAs) which, in turn, inhibit the intestinal FXR-FGF15 signaling pathway, resulting in increased hepatic production and fecal excretion of BAs, reduced hepatic cholesterol, and decreased lipogenesis. The inhibition of intestinal FXR-FGF15 signaling is accompanied by increased gene expression of enzymes in the alternative BA synthetic pathway, production of hepatic chenodeoxycholic acid, activation of hepatic FXR, and hepatic lipolysis. Our results shed light into the mechanisms behind the cholesterol- and lipid-lowering effects of Pu-erh tea, and suggest that decreased intestinal BSH microbes and/or decreased FXR-FGF15 signaling may be potential anti-hypercholesterolemia and anti-hyperlipidemia therapies.

The Wnt/beta-catenin signalling pathway appears to operate to maintain the undifferentiated state of preadipocytes by inhibiting adipogenic gene expression. To define the mechanisms regulating suppression of Wnt/beta-catenin signalling, we analysed the beta-catenin expression in response to activation of transcription factors that regulate adipogenesis. The results show an extensive down-regulation of nuclear beta-catenin that occurs during the first few days of differentiation of 3T3-L1 preadipocytes and coincides with the induction of the adipogenic transcription factors, C/EBPbeta (CCAAT-enhancer-binding protein) and PPARgamma (peroxisome-proliferator-activated receptor). To assess the role of each of these factors in this process, we conditionally overexpressed C/EBPbeta in Swiss mouse fibroblasts using the TET-off system. Abundant expression of C/EBPbeta alone had minimal effect on beta-catenin expression, whereas expression of C/EBPbeta, in the presence of dexamethasone, induced PPARgamma expression and caused a measurable decrease in beta-catenin. In addition, exposure of cells expressing both C/EBPbeta and PPARgamma to a potent PPARgamma ligand resulted in an even greater decrease in beta-catenin by mechanisms that involve the proteasome. Our studies also suggest a reciprocal relationship between PPARgamma activity and beta-catenin expression, since ectopic production of Wnt-1 in preadipocytes blocked the induction of PPARgamma gene expression. Moreover, by suppressing beta-catenin expression, ectopic expression of PPARgamma in Wnt-1-expressing preadipocytes rescued the block in adipogenesis after their exposure to the PPARgamma ligand, troglitazone.

Studies have demonstrated cross talk between ␤-catenin and peroxisome proliferator-activated receptor ␥ (PPAR␥) signaling pathways. Specifically, activation of PPAR␥ induces the proteasomal degradation of ␤-catenin in cells that express an adenomatous polyposis coli-containing destruction complex. In contrast, oncogenic ␤-catenin is resistant to such degradation and inhibits the expression of PPAR␥ target genes. In the present studies, we demonstrate a functional interaction between ␤-catenin and PPAR␥ that involves the T-cell factor (TCF)/lymphocyte enhancer factor (LEF) binding domain of ␤-catenin and a catenin binding domain (CBD) within PPAR␥. Mutation of K312 and K435 in the TCF/LEF binding domain of an oncogenic ␤-catenin (S37A) significantly reduces its ability to interact with and inhibit the activity of PPAR␥. Furthermore, these mutations render S37A ␤-catenin susceptible to proteasomal degradation in response to activation of PPAR␥. Mutation of F372 within the CBD (helices 7 and 8) of PPAR␥ disrupts its binding to ␤-catenin and significantly reduces the ability of PPAR␥ to induce the proteasomal degradation of ␤-catenin. We suggest that in normal cells, PPAR␥ can function to suppress tumorigenesis and/or Wnt signaling by targeting phosphorylated ␤-catenin to the proteasome through a process involving its CBD. In contrast, oncogenic ␤-catenin resists proteasomal degradation by inhibiting PPAR␥ activity, which requires its TCF/LEF binding domain.

SUMMARY Rapidly proliferating leukemic progenitor cells consume substantial glucose that may lead to glucose insufficiency in bone marrow. We show that acute myeloid leukemia (AML) cells are prone to fructose utilization with an upregulated fructose transporter GLUT5, compensating for glucose deficiency. Notably, AML patients with upregulated transcription of GLUT5-encoding gene SLC2A5 or increased fructose utilization have poor outcomes. Pharmacological blockage of fructose uptake ameliorates leukemic phenotypes and potentiates the cytotoxicity of antileukemic agent, Ara-C. In conclusion, this study highlights enhanced fructose utilization as a metabolic feature of AML and a potential therapeutic target.