Cholesterol is one of the hallmarks of animals. In vertebrates, the cholesterol synthesis pathway (CSP) is the primary source of cholesterol that has numerous structural and regulative roles [1]. Nevertheless, the few invertebrates tested for cholesterol synthesis show complete sterol auxotrophy [2-6], raising questions about how animals thrive without cholesterol synthesis and about the prevalence of sterol auxotrophy in animals. In the nematode Caenorhabditis elegans (C. elegans), sterols are the precursors of the steroid hormone dafachronic acid that coordinates development to adulthood [7,8]; thus, sterol-deprived C. elegans arrest at the diapause ''dauer'' larval stage [9]. Using this system, we have identified a pathway that converts plant and fungal sterols into cholesterol through the activity of enzymes with sequence similarity to specific human CSP enzymes. Based on this finding, we propose that two critical steps shaped the evolution of animal sterol auxotrophy: (1) the loss of the orthologs of the first three enzymes of the CSP and (2) the co-opting of other downstream enzymes of the CSP for the utilization of dietary sterols. Using this mechanistic signature, we studied the evolution of cholesterol auxotrophy across the animal kingdom. Complete sets of CSP enzymes in basal animals suggest that the loss of cholesterol synthesis occurred during animal evolution. A sterol auxothropy signature in the genomes of many invertebrates, including nematodes and most arthropods, suggests widespread cholesterol auxotrophy in animals. Thus, we propose that this co-opted pathway supports widespread cholesterol auxotrophy by interkingdom interactions between cholesterol-auxotrophic animals and sterol-producing fungi and plants.

The mevalonate pathway is the primary target of the cholesterol-lowering drugs statins, some of the most widely prescribed medicines of all time. The pathway's enzymes not only catalyze the synthesis of cholesterol but also of diverse metabolites such as mitochondrial electron carriers and isoprenyls. Recently, it has been shown that one type of mitochondrial stress response, the UPR, can protect yeast, , and cultured human cells from the deleterious effects of mevalonate pathway inhibition by statins. The mechanistic basis for this protection, however, remains unknown. Using, we found that the UPR does not directly affect the levels of the statin target HMG-CoA reductase, the rate-controlling enzyme of the mevalonate pathway in mammals. Instead, in the UPR upregulates the first dedicated enzyme of the pathway, HMG-CoA synthase (HMGS-1). A targeted RNA interference (RNAi) screen identified two UPR transcription factors, ATFS-1 and DVE-1, as regulators of HMGS-1 A comprehensive analysis of the pathway's enzymes found that, in addition to HMGS-1, the UPR upregulates enzymes involved with the biosynthesis of electron carriers and geranylgeranylation intermediates. Geranylgeranylation, in turn, is requisite for the full execution of the UPR 3response. Thus, the UPR acts in at least three coordinated, compensatory arms to upregulate specific branches of the mevalonate pathway, thereby alleviating mitochondrial stress. We propose that statin-mediated inhibition of the mevalonate pathway blocks this compensatory system of the UPR and consequentially impedes mitochondrial homeostasis. This effect is likely one of the principal bases for the adverse side effects of statins.

The interplay between heart failure and cancer represents a double-edged sword. Whereas cardiac remodeling promotes cancer progression, tumor growth suppresses cardiac hypertrophy and reduces fibrosis deposition. Whether these two opposing interactions are connected awaits to be determined. In addition, it is not known whether cancer affects solely the heart, or if other organs are affected as well. To explore the dual interaction between heart failure and cancer, we studied the human genetic disease Duchenne Muscular Dystrophy (DMD) using the MDX mouse model. We analyzed fibrosis and cardiac function as well as molecular parameters by multiple methods in the heart, diaphragm, lungs, skeletal muscles, and tumors derived from MDX and control mice. Surprisingly, cardiac dysfunction in MDX mice failed to promote murine cancer cell growth. In contrast, tumor-bearing MDX mice displayed reduced fibrosis in the heart and skeletal and diaphragm muscles, resulting in improved cardiac function. The latter is at least partially mediated via M2 macrophage recruitment to the heart and diaphragm muscles. Collectively, our data support the notion that the effect of heart failure on tumor promotion is independent of the improved cardiac function in tumor-bearing mice. Reduced fibrosis in tumor-bearing MDX mice stems from the suppression of new fibrosis synthesis and the removal of existing fibrosis. These findings offer potential therapeutic strategies for DMD patients, fibrotic diseases, and cardiac dysfunction.

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Heart failure and cancer are known to share common risk factors. Nevertheless, until recently, these two were considered separate diseases. Nevertheless, it appears that heart failure and cancer are more connected than initially anticipated. The interplay between heart failure and cancer represents a double-edged sword. While Cardiac remodeling promotes cancer progression, tumor growth suppresses cardiac hypertrophy and reduces fibrosis deposition. Whether these two opposing interactions are connected is currently unknown. In addition, the experimental setup used was unable to distinguish whether tumor growth suppresses de novo fibrosis synthesis or is capable of dissolving existing fibrosis as well. Here we studied a clinically relevant human disease, Duchenne Muscular Dystrophy (DMD), using MDX mouse as a model for a fibrotic disease in multiple organs. Duchenne patients suffer from fibrosis of the skeletal, cardiac, and diaphragm muscles leading to cardiomyopathy, and respiratory failure with no cure. To study the mutual interaction between heart failure and cancer, we implanted murine cancer cells in MDX mice and monitored tumor growth, cardiac function, and fibrosis. Surprisingly, cardiac dysfunction failed to promote cancer progression in MDX mice. In contrast, MDX tumor-bearing mice displayed reduced fibrosis in the lungs, heart and diaphragm muscles resulting in an improvement of cardiac contractile function. The latter is at least partially mediated via macrophage polarization towards M2 in the heart and diaphragm muscles. Collectively, our data support the notion that tumor promotion due to heart failure is an independent of cardiac dysfunction amelioration by tumor growth. Additionally, these results suggest that the reduced overall fibrosis in tumor-bearing MDX mice represents suppression of de novo fibrosis deposition as well as dissolving existing fibrosis in the heart and diaphragm muscles. Harnessing tumor paradigms may provide novel therapeutic strategies for DMD patients, human fibrotic diseases, and cardiac dysfunction.