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Author(s): Stanley W. K. Ng [sup.1] , Foad J. Rouhani [sup.1] [sup.2] , Simon F. Brunner [sup.1] , Natalia Brzozowska [sup.1] , Sarah J. Aitken [sup.3] [sup.4] [sup.5] , Ming [...], The progression of chronic liver disease to hepatocellular carcinoma is caused by the acquisition of somatic mutations that affect 20-30 cancer genes.sup.1-8. Burdens of somatic mutations are higher and clonal expansions larger in chronic liver disease.sup.9-13 than in normal liver.sup.13-16, which enables positive selection to shape the genomic landscape.sup.9-13. Here we analysed somatic mutations from 1,590 genomes across 34 liver samples, including healthy controls, alcohol-related liver disease and non-alcoholic fatty liver disease. Seven of the 29 patients with liver disease had mutations in FOXO1, the major transcription factor in insulin signalling. These mutations affected a single hotspot within the gene, impairing the insulin-mediated nuclear export of FOXO1. Notably, six of the seven patients with FOXO1.sup.S22W hotspot mutations showed convergent evolution, with variants acquired independently by up to nine distinct hepatocyte clones per patient. CIDEB, which regulates lipid droplet metabolism in hepatocytes.sup.17-19, and GPAM, which produces storage triacylglycerol from free fatty acids.sup.20,21, also had a significant excess of mutations. We again observed frequent convergent evolution: up to fourteen independent clones per patient with CIDEB mutations and up to seven clones per patient with GPAM mutations. Mutations in metabolism genes were distributed across multiple anatomical segments of the liver, increased clone size and were seen in both alcohol-related liver disease and non-alcoholic fatty liver disease, but rarely in hepatocellular carcinoma. Master regulators of metabolic pathways are a frequent target of convergent somatic mutation in alcohol-related and non-alcoholic fatty liver disease. Whole-genome sequencing analysis of somatic mutations in liver samples from patients with chronic liver disease identifies driver mutations in metabolism-related genes such as FOXO1, and shows that these variants frequently exhibit convergent evolution.

Introduction Caffeine is the most widely consumed psychoactive substance in the world (by about 80% of the population) via dietary intake from coffee, tea, and soda beverages. Its popularity derives [...], Caffeine is the most widely consumed psychoactive substance in the world. Strikingly, the molecular pathways engaged by its regular consumption remain unclear. We herein addressed the mechanisms associated with habitual (chronic) caffeine consumption in the mouse hippocampus using untargeted orthogonal omics techniques. Our results revealed that chronic caffeine exerts concerted pleiotropic effects in the hippocampus at the epigenomic, proteomic, and metabolomic levels. Caffeine lowered metabolism-related processes (e.g., at the level of metabolomics and gene expression) in bulk tissue, while it induced neuron-specific epigenetic changes at synaptic transmission/plasticity-related genes and increased experience-driven transcriptional activity. Altogether, these findings suggest that regular caffeine intake improves the signal-to-noise ratio during information encoding, in part through fine-tuning of metabolic genes, while boosting the salience of information processing during learning in neuronal circuits.

Author(s): Vronique Frattini [1]; Stefano M. Pagnotta [1, 2]; Tala [1]; Jerry J. Fan [3, 4]; Marco V. Russo [1]; Sang Bae Lee [1]; Luciano Garofano [1, 2, 5]; Jing [...]

Paracardial fat mass There is an extensive body of literature showing that different fat depots have different physiologic functions (1). Far from being a passive storage space for excess calories, [...], Different fat depots have different physiologic functions. In a provocative study published in this issue of the JCI, Petrosino et al. investigate the role of paracardial fat in whole-body metabolism and exercise physiology. Petrosino et al. show that paracardial fat samples from older mice or mice fed a Western diet had decreased levels of alcohol dehydrogenase 1 (ADH1). Paracardial fat samples from humans with obesity also had decreased levels of ADH1 mRNA, supporting the translational relevance. Additional experiments with Adh1-KO mice and surgical fat transplantation experiments provide additional mechanistic insight. Paracardial fat may regulate exercise performance by altering circulating metabolites and/or endocrine effects. ADH1 appears to regulate the mitochondrial content of paracardial fat, a mechanism mediated by retinaldehyde. When ADH1 is active, the paracardial fat has characteristics of brown fat, which is beneficial for exercise performance. Further research is warranted to determine the translational potential of these findings, such as whether removing paracardial fat at the time of open-heart surgery might improve recovery time by increasing exercise capacity.