This article is available online at http://www.jlr.org deposition of toxic lipid intermediates in the heart that may have deleterious effects ("lipotoxicity") on myocardial structure and function ( 2 ). Studies using mouse models of increased myocardial lipid availability showed that increasing lipid accumulation directly in cardiomyocytes (CMs) was suffi cient to induce lipotoxic cardiomyopathy and premature cell death independently of systemic or neurohumoral effects of obesity ( 3-5 ). However, gaps remain in our mechanistic understanding of the interactions between lipid accumulation and cardiac dysfunction and the impact of lipotoxicity on cardiac autophagy has been relatively understudied.Macroautophagy (hereafter "autophagy") is a catabolic process wherein cytoplasmic materials are delivered to lysosomes in double-membrane structures called autophagosomes for degradation ( 6 ). Autophagy regulates lipid metabolism in multiple tissues ( 7-9 ). Impaired autophagy Abstract Autophagy is a catabolic process involved in maintaining energy and organelle homeostasis. The relationship between obesity and the regulation of autophagy is cell type specifi c. Despite adverse consequences of obesity on cardiac structure and function, the contribution of altered cardiac autophagy in response to fatty acid overload is incompletely understood. Here, we report the suppression of autophagosome clearance and the activation of NADPH oxidase (Nox)2 in both high fat-fed murine hearts and palmitate-treated H9C2 cardiomyocytes (CMs). Defective autophagosome clearance is secondary to superoxidedependent impairment of lysosomal acidifi cation and enzyme activity in palmitate-treated CMs. Inhibition of Nox2 prevented superoxide overproduction, restored lysosome acidifi cation and enzyme activity, and reduced autophagosome accumulation in palmitate-treated CMs. Palmitate-induced Nox2 activation was dependent on the activation of classical protein kinase Cs (PKCs), specifi cally PKC  II. These fi ndings reveal a novel mechanism linking lipotoxicity with a PKC  -Nox2-mediated impairment in pH-dependent lysosomal enzyme activity that diminishes autophagic turnover in CMs. Obesity is an independent risk factor for CVD ( 1 ). A prominent factor in obesity-related cardiomyopathy is the ectopic
The 2016 icsid award in Urbaser v. Argentina affirmed for the first time the possibility of a counterclaim in investment arbitration based on an international investor obligation under the human right to water. But to denounce a break-through and fundamental change in both international investment and human rights law would be premature. This article deconstructs the award's reasoning and sheds light on its doctrinal fallacies, in particular the award's unclear construction of the integration of a human rights obligation into investment arbitration and its misled argumentation on the existence of an international human rights obligation of private actors under the human right to water. Concluding that the award cannot be sustained under the current state of international law, the article then reflects on the potential of the award's conception of human rights counterclaims for the future of international investment law and international human rights law.
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