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  • Importantly the regulation of the

    2022-01-21

    Importantly, the regulation of the Hippo pathway by metabolic networks, such as by glycolysis39, 40, hexosamine biosynthesis41, 42, and mevalonate synthesis43, 44, as well as by nutrient-sensing pathways including AMP-activated protein kinase (AMPK) 40, 45, 46 and mTOR 47, 48, 49, 50, was recently discovered, suggesting a functional role for the Hippo pathway in cellular metabolism. This is a key advance in our knowledge of the Hippo pathway from the early characterization of its effects on organ size to the elucidation of the specific pathways and biochemical processes that are involved in cellular and systemic metabolism (see below).
    The Hippo Pathway in Cellular Metabolism
    Hippo Signaling in the Pancreas A distinct mechanism of Hippo regulation has recently been discovered in the endocrine and exocrine parts of the pancreas. The exocrine fraction contains acinar and ductal Pentostatin that produce enzymes required for nutrient digestion, and the smaller endocrine fraction (about 1–2% of the volume of the whole pancreas) harbors the islets of Langerhans cells that produce and secrete hormones to maintain glucose homeostasis and metabolism: predominantly insulin produced by β cells, glucagon by α cells, and somatostatin by δ cells [63]. The pancreas undergoes important changes during embryonic development, which are either paralleled or even regulated by the expression of the Hippo terminal effector YAP, which is highly expressed throughout the pancreas in the multipotent progenitor stage 9, 14, 15, 16, 64, 65. By contrast, after differentiation it remains expressed in ductal and centroacinar cells at low levels [14], but is fully excluded from the endocrine islet cells at the time when key endocrine progenitor transcription factor and marker Ngn3 becomes expressed [15]. Because YAP re-expression in human islets 13, 15 specifically increases proliferation without loss of functional genes for insulin production, it is likely that the absence of YAP, one of the ‘disallowed’ genes in the β cell 66, 67, is responsible for their extremely low proliferative capacity. Pathologically elevated YAP expression in the pancreas leads to malignant growth and severe pancreatic ductal adenocarcinoma [68], but pancreatic/β cell deletion of MST1 [11] or both MST1 and 2 does not induce tumors; only a moderate increase in proliferation with disorganized morphology [16] and acinar dedifferentiation [14] was observed, which suggests that MST1/2 also has non-canonical functions that are independent of YAP. In contrast to the absence of the Hippo executer YAP in the endocrine pancreas, more upstream components of the Hippo pathway are direct regulators of apoptosis in β cells, such as NF2/Merlin 12, 17, MST1 10, 11, 69, and YAP 13, 70. Specifically, MST1 is activated under diabetic conditions in vitro as well as in isolated islets from patients with T2D and from both T1D and T2D mouse models. It seems here that a continuous activation loop between active caspase 3, the master apoptosis executer, and cleaved MST1 (the active form of MST1) enables the potentiation of an apoptotic cascade under chronic metabolic or inflammatory stress, leading to β cell death. Furthermore, MST1 kinase directly phosphorylates the crucial β cell transcription factor PDX1 (that is important for β cell homeostasis throughout the lifetime of the animal, as well as for β cell development, survival, and function [71]), leading to its ubiquitination and degradation, and consequently to loss of insulin production and secretion. MST1 deficiency profoundly restores β cell function and survival, and leads to restoration of β cell mass and normoglycemia in mouse models of diabetes 10, 11. This, as well as the detailed functions and regulation of the Hippo pathway in the pancreas, have been recently reviewed [9].
    The Hippo Pathway Regulates Liver Metabolism Hippo signaling is a key established pathway in the regulation of hepatic size, proliferation, apoptosis, and stress response, as well as in liver regeneration; its dysregulation leads to liver tumorigenesis and dedifferentiation on the one hand, and to severe hepatocyte damage and defective repair on the other (Box 2) [72]. The liver plays a central role in global glucose homeostasis and metabolic adaptations through the regulation of glucose and lipid metabolism, and its failure (i.e., hepatic insulin resistance or fat accumulation – hepatosteatosis) is a common pathogenic signature Pentostatin of several metabolic disorders such as obesity, T2D, and NAFLD 2, 5. Because growth signals are tightly regulated by cellular metabolism, it is therefore not surprising that recent studies identified Hippo as a modulator of metabolism in metabolically active tissues, specifically in the liver.