SummarySex impacts on liver physiology with severe consequences for energy metabolism and response to xenobiotic, hepatic, and extra-hepatic diseases. The comprehension of the biology subtending sex-related hepatic differences is therefore very relevant in the medical, pharmacological, and dietary perspective. The extensive application of metabolomics paired to transcriptomics here shows that, in the case of short-term fasting, the decision to maintain lipid synthesis using amino acids (aa) as a source of fuel is the key discriminant for the hepatic metabolism of male and female mice. Pharmacological and genetic interventions indicate that the hepatic estrogen receptor (ERα) has a key role in this sex-related strategy that is primed around birth by the aromatase-dependent conversion of testosterone into estradiol. This energy partition strategy, possibly the result of an evolutionary pressure enabling mammals to tailor their reproductive capacities to nutritional status, is most important to direct future sex-specific dietary and medical interventions.

ach tissue has a specific composition of its extracellular matrix (ECM), which is associated with distinctive physical and mechanical properties. These mechanical properties are important for tissue structure, but also control cell function in physiology and disease 1,2. Cells sense the mechanical properties of the ECM through integrin receptors, and measure them by adjusting the contractility of their F-actin cytoskeleton: contractility is maximal when cells are free to spread on stiff ECM substrata, while it is progressively decreased on a soft ECM or in conditions of limited spreading 1. This is sufficient to control the switch between proliferation, differentiation and death in very diverse cell types, by regulating intracellular signalling pathways such as YAP (Yes-associated protein)/TAZ (transcriptional co-activator with PDZ-binding motif, also known as WWTR1) 3,4 and SRF (serum response factor) 5,6. In support of this model, inhibition of key players that maintain F-actin contractility including the small GTPase RHO, ROCK (RHO kinase), MLCK (myosin light chain kinase) and non-muscle myosin (NMII) induce similar responses to a soft ECM 1. Yet, which other general aspects of cell biology are regulated by mechanical cues, and through which mechanism(s), remain largely unexplored. This is especially true in the case of metabolism, a fundamental engine that is constantly remodelled to match the energetic and biosynthetic requirements of the cell, whose connections to mechanical cues are only starting to emerge 7,8. Results Actomyosin regulates lipid metabolism. To test in an unbiased manner the possibility that actomyosin contractility regulates metabolism we used global metabolomics to compare cells in conditions of high contractility (plated on plastics) with cells in conditions of low contractility, by inhibiting ROCK and MLCK. Analysis of steady-state levels of multiple metabolites indicated clear differences between controls and treated cells (Fig. 1a and Supplementary

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Aims PCSK9 is secreted into the circulation, mainly by the liver, and interacts with low-density lipoprotein receptor (LDLR) homologous and non-homologous receptors, including CD36, thus favouring their intracellular degradation. As PCSK9 deficiency increases the expression of lipids and lipoprotein receptors, thus contributing to cellular lipid accumulation, we investigated whether this could affect heart metabolism and function. Methods and results Wild-type (WT), Pcsk9 KO, Liver conditional Pcsk9 KO and Pcsk9/Ldlr double KO male mice were fed for 20 weeks with a standard fat diet and then exercise resistance, muscle strength, and heart characteristics were evaluated. Pcsk9 KO presented reduced running resistance coupled to echocardiographic abnormalities suggestive of heart failure with preserved ejection fraction (HFpEF). Heart mitochondrial activity, following maximal coupled and uncoupled respiration, was reduced in Pcsk9 KO mice compared to WT mice and was coupled to major changes in cardiac metabolism together with increased expression of LDLR and CD36 and with lipid accumulation. A similar phenotype was observed in Pcsk9/Ldlr DKO, thus excluding a contribution for LDLR to cardiac impairment observed in Pcsk9 KO mice. Heart function profiling of the liver selective Pcsk9 KO model further excluded the involvement of circulating PCSK9 in the development of HFpEF, pointing to a possible role locally produced PCSK9. Concordantly, carriers of the R46L loss-of-function variant for PCSK9 presented increased left ventricular mass but similar ejection fraction compared to matched control subjects. Conclusion PCSK9 deficiency impacts cardiac lipid metabolism in an LDLR independent manner and contributes to the development of HFpEF.

Accumulation of DNA lesions causing transcription stress is associated with natural and accelerated aging and culminates with profound metabolic alterations. Our understanding of the mechanisms governing metabolic redesign upon genomic instability, however, is highly rudimentary. Using Ercc1-defective mice and Xpg knock-out mice, we demonstrate that combined defects in transcription-coupled DNA repair (TCR) and in nucleotide excision repair (NER) directly affect bioenergetics due to declined transcription, leading to increased ATP levels. This in turn inhibits glycolysis allosterically and favors glucose rerouting through the pentose phosphate shunt, eventually enhancing production of NADPH-reducing equivalents. In NER/TCR-defective mutants, augmented NADPH is not counterbalanced by increased production of pro-oxidants and thus pentose phosphate potentiation culminates in an over-reduced redox state. Skin fibroblasts from the TCR disease Cockayne syndrome confirm results in animal models. Overall, these findings unravel a mechanism connecting DNA damage and transcriptional stress to metabolic redesign and protective antioxidant defenses.