Investigating the effect of chronic activation of AMP-activated protein kinase in the liver

Obesity and its associated complications, are an increasing global problem. Non-alcoholic fatty liver disease (NAFLD), the hepatic component of the Metabolic Syndrome currently affects an estimated 25% of the world’s population, with 2% of those affected dying from a NAFLD liver related cause, such as hepatocellular cancer (HCC). AMP-activated protein kinase (AMPK), a master regulator of energy homeostasis that regulates anabolic and catabolic pathways in response to ATP depletion has received substantial attention as a therapeutic target in treatment of the Metabolic Syndrome. More recently, a growing number of studies have focussed on the role of AMPK in cancer. This study has characterised a novel, activating mutation in the γ1 subunit of AMPK (D316A). Mice which express this mutation specifically in the liver (D316-Tg) have been used to investigate the effects of chronic hepatic AMPK activation under basal conditions and in response to the metabolic stresses of hypercaloric, high fat and lipogenic, high fructose diets. D316A-Tg mice have also been crossed with mice with liver specific Phospatase and tensin homologue (Pten) loss to evaluate the role of AMPK in NAFLD related HCC. Fatty acid synthesis was reduced in hepatocytes isolated from D316A-Tg mice and these mice were protected from hepatic steatosis under lipogenic conditions. Fatty acid oxidation in hepatocytes was unaffected by increased AMPK activity and correspondingly D316A-Tg mice were not protected from hepatic lipid accumulation, following high fat feeding. Increased hepatic AMPK activity also attenuated steatohepatitis and had a marked inhibitory effect on tumourgenesis in mice with liver specific Pten loss. Further work is required to elucidate the precise role of AMPK in tumour development. However, the findings of this study suggest that activation of AMPK in the liver may inhibit NAFLD progression and tumourgenesis and support the development of pharmacological, specific AMPK activators for use in these settings.Open Acces

Refinement of the associations between risk of colorectal cancer and polymorphisms on chromosomes 1q41 and 12q13.13

In genome-wide association studies (GWASs) of colorectal cancer, we have identified two genomic regions in which pairs of tagging-single nucleotide polymorphisms (tagSNPs) are associated with disease; these comprise chromosomes 1q41 (rs6691170, rs6687758) and 12q13.13 (rs7163702, rs11169552). We investigated these regions further, aiming to determine whether they contain more than one independent association signal and/or to identify the SNPs most strongly associated with disease. Genotyping of additional sample sets at the original tagSNPs showed that, for both regions, the two tagSNPs were unlikely to identify a single haplotype on which the functional variation lay. Conversely, one of the pair of SNPs did not fully capture the association signal in each region. We therefore undertook more detailed analyses, using imputation, logistic regression, genealogical analysis using the GENECLUSTER program and haplotype analysis. In the 1q41 region, the SNP rs11118883 emerged as a strong candidate based on all these analyses, sufficient to account for the signals at both rs6691170 and rs6687758. rs11118883 lies within a region with strong evidence of transcriptional regulatory activity and has been associated with expression of PDGFRB mRNA. For 12q13.13, a complex situation was found: SNP rs7972465 showed stronger association than either rs11169552 or rs7136702, and GENECLUSTER found no good evidence for a two-SNP model. However, logistic regression and haplotype analyses supported a two-SNP model, in which a signal at the SNP rs706793 was added to that at rs11169552. Post-GWAS fine-mapping studies are challenging, but the use of multiple tools can assist in identifying candidate functional variants in at least some cases

Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements