Partner in fat metabolism: role of KLFs in fat burning and reproductive behavior

The abnormalities caused by excess fat accumulation can result in pathological conditions which are linked to several interrelated diseases, such as cardiovascular disease and obesity. This set of conditions, known as metabolic syndrome, is a global pandemic of enormous medical, economic, and social concern affecting a significant portion of the world’s population. Although genetics, physiology and environmental components play a major role in the onset of disease caused by excessive fat accumulation, little is known about how or to what extent each of these factors contributes to it. The worm, Caenorhabditis elegans offers an opportunity to study disease related to metabolic disorder in a developmental system that provides anatomical and genomic simplicity relative to the vertebrate animals and is an excellent eukaryotic genetic model which enable us to answer the questions concerning fat accumulation which remain unresolved. The stored triglycerides (TG) provide the primary source of energy during periods of food deficiency. In nature, lipid stored as TGs are hydrolyzed into fatty acids which are broken down through β-oxidation to yield acetyl-CoA. Our recent study suggests that a member of C. elegans Krüppel-like factor, klf-3 regulates lipid metabolism by promoting FA β-oxidation and in parallel may contribute in normal reproduction and fecundity. Genetic and epigenetic factors that influence this pathway may have considerable impact on fat related diseases in human. Increasing number of studies suggest the role of mammalian KLFs in adipogenesis. This functional conservation should guide our further effort to explore C. elegans as a legitimate model system for studying the role of KLFs in many pathway components of lipid metabolism

Lactate/pyruvate transporter MCT-1 is a direct Wnt target that confers sensitivity to 3-bromopyruvate in colon cancer

BACKGROUND: There is increasing evidence that oncogenic Wnt signaling directs metabolic reprogramming of cancer cells to favor aerobic glycolysis or Warburg metabolism. In colon cancer, this reprogramming is due to direct regulation of pyruvate dehydrogenase kinase 1 (PDK1) gene transcription. Additional metabolism genes are sensitive to Wnt signaling and exhibit correlative expression with PDK1. Whether these genes are also regulated at the transcriptional level, and therefore a part of a core metabolic gene program targeted by oncogenic WNT signaling, is not known. RESULTS: Here, we identify monocarboxylate transporter 1 (MCT-1; encoded by SLC16A1) as a direct target gene supporting Wnt-driven Warburg metabolism. We identify and validate Wnt response elements (WREs) in the proximal SLC16A1 promoter and show that they mediate sensitivity to Wnt inhibition via dominant-negative LEF-1 (dnLEF-1) expression and the small molecule Wnt inhibitor XAV939. We also show that WREs function in an independent and additive manner with c-Myc, the only other known oncogenic regulator of SLC16A1 transcription. MCT-1 can export lactate, the byproduct of Warburg metabolism, and it is the essential transporter of pyruvate as well as a glycolysis-targeting cancer drug, 3-bromopyruvate (3-BP). Using sulforhodamine B (SRB) assays to follow cell proliferation, we tested a panel of colon cancer cell lines for sensitivity to 3-BP. We observe that all cell lines are highly sensitive and that reduction of Wnt signaling by XAV939 treatment does not synergize with 3-BP, but instead is protective and promotes rapid recovery. CONCLUSIONS: We conclude that MCT-1 is part of a core Wnt signaling gene program for glycolysis in colon cancer and that modulation of this program could play an important role in shaping sensitivity to drugs that target cancer metabolism. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s40170-016-0159-3) contains supplementary material, which is available to authorized users