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  • MAP Ks act at the level

    2021-12-06

    MAP4Ks act at the level of MST1/2 to phosphorylate LATS1/2 and regulate the Hippo pathway (Box 1). Of particular interest is the involvement of MAP4K4, a key metabolic regulator [88] and common polymorphisms in the MAP4K4 locus are associated with T2D and insulin resistance [89] in adipogenesis. In KU14R to the proadipogenic action of MST/LATS, loss of MAP4K4 upregulates the expression of key adipogenic transcription factors such as CCAAT enhancer-binding proteins (C/EBPα and C/EBPβ) and PPARγ, as well as glucose transporter GLUT4; all lead to increased adipogenesis and glucose uptake [90]. Whether canonical Hippo signaling (i.e., LATS1/2 or YAP) contributes to the regulation of adipogenesis by MAP4K4 has not been investigated and warrants further investigation. All these interesting findings start to establish Hippo as strong regulator of adipogenesis (Figure 3B). Of note, MST1 activity is highly upregulated in deposits of excess fat in mice subjected to HFD feeding [26]. Such MST1 hyperactivation, at least under conditions of high-fat feeding, has been postulated as an activator of JNK–FOXO1 signaling to promote chronic fat inflammation and insulin resistance [26] because MST1-induced JNK [11] or FOXO1 [91] activation has been previously reported.
    Hippo Pathway in the Metabolically Stressed Heart Genetic manipulation of Hippo components such as MST, LATS, NF2, and YAP strongly modulates cardiac apoptosis, proliferation, and regeneration. This suggests that the Hippo pathway is a major regulator of several key cellular processes in the heart (Box 3) 92, 93. Metabolic dysfunction and disorders such as diabetes have dramatically increased and are highest risk factors for cardiac infarction, cardiomyopathy, and other cardiovascular disorders. In a context of high nutrition as well as metabolic stress, functional maladaptation occurs frequently in pancreatic islets, in insulin-responsive tissues, and in the cardiovascular system. The Hippo pathway is highly induced during diabetes-associated cardiac injury, and Hippo inactivation rescues cardiac cell survival in mouse models of diabetes 30, 31, 32, 94. Deleterious disproportional regulation of autophagy and apoptosis, key modulators of cellular and global metabolism and turnover, respectively, has often been observed in diabetic cardiomyopathy [95] and in atherosclerotic plaque formation [33]; in other words deficient autophagy fails to clear injured cells, while apoptosis is increased. Restoration of Parkin, which controls recycling of damaged mitochondria in the heart, is an essential mechanism of cardiac repair [96]. Several recent studies have established regulation of autophagy by Hippo in the heart during diabetes-associated cardiac failure 30, 31, 32, 94, 97 (Box 3). Molecular analyses show that MST1-induced direct phosphorylation of Beclin 1, a key player in the regulation of both autophagy and apoptosis, promotes the Beclin 1–Bcl-2 interaction and fosters proapoptotic Bax activation, and thus participates in both the reduction of autophagy and the induction of apoptosis, thereby promoting cardiac cell death [97]. Loss of MST1 in the diabetic streptozotocin mouse model restores autophagy through increased LC3 expression, decreased p62 expression, and enhanced autophagosome formation [31] as a result of disrupted Beclin1–Bcl-2 interaction, and conversely enhanced interaction between Bcl-2 and Bax, which directly prevents apoptosis in Mst1 knockout mice [31]. This conclusion is fully substantiated by an in vitro study in which cardiac microvascular endothelial cells (CMECs) were cultured under high glucose, which induced MST1 activation and reduced Beclin 1 expression together with diabetic coronary microvascular dysfunction and apoptosis. By contrast, MST1 depletion reduced apoptosis and restored autophagic flux through an elevated LC3-II/LC3-1 ratio and decreased p62 expression. Moreover, MST1 deficiency improves cardiac microvessel integrity and cardiac function in diabetic mice [32]. Another study also found diminished autophagic activity in atherosclerotic plaques; MST1 promotes atherosclerosis and atherosclerotic plaque formation [33]. By contrast, loss of MST1 in the Apoe−/− mouse model of atherosclerosis reduces lipid droplets in plaques, atherosclerotic area, and macrophage accumulation [33]. As already described during heart failure [31], MST1 depletion increases Beclin 1 and LC3II, and decreases p62, in aortic atherosclerosis, and thus normalizes autophagy and reduces macrophage-mediated apoptosis. All these important findings suggest intimate crosstalk between Hippo–MST1 signaling and autophagy in the regulation of death and repair in the metabolically stressed heart. The protective effects of MST1 depletion in the heart seem to be also facilitated by an elevation of sirtuin 3 (SIRT3) signaling [30]. SIRT3 is a mitochondrial matrix protein, where it acts as a mitochondrial tumor suppressor. It can promote angiogenesis and cardiac function, and has been shown to protect against diabetic cardiomyopathy and cardiomyocyte death 98, 99.