A recent novel and important finding is that YAP

A recent novel and important finding is that YAP connects cellular growth with anabolism; YAP suppresses the transcriptional induction of genes which importantly regulate gluconeogenesis in the liver; namely glucose-6-phosphatase catalytic subunit (G6PC) and phosphoenolpyruvate carboxykinase 1 (PCK1), through the inhibition of peroxisome proliferator-activated receptor γ coactivator 1α (PGC1-α), a key regulator of energy metabolism [22]. While YAP knockdown potentiates glucagon-induced G6PC and PCK1, its constitutive overexpression reduces hepatic gluconeogenic gene expression, which results in lower blood glucose levels and improved glucose tolerance (Figure 3A) [22]. Suppression of gluconeogenesis is only effective in the presence of glucagon. This study unveils a previously uncharacterized function of hepatic YAP in regulating glucose homeostasis in mice that is independent of its classical role as a growth promoter. The effect of YAP to reduce blood glucose to support intracellular growth is also supported by the observation that in Drosophila insulin activates YAP, and thus both in concert support proliferation [73]. Analysis of hepatocellular carcinoma and mammalian cell culture experiments support the interconnection of insulin/YAP pathways because both pathways were simultaneously activated and induce the major nutrient-sensing pathway mTOR [73]. Such YAP–insulin signaling crosstalk is a bottleneck in the development of liver disease (i.e., NAFLD) and progression to liver cancer. Insulin receptor substrate 2 (IRS2), an integral component of insulin signaling pathway, was identified as a direct transcriptional target of YAP, and elevated YAP/TAZ expression correlates with a high level of IRS2 in human hepatocellular carcinoma. In mice, uncontrolled YAP activation through deletion of MST-associated protein SAV1 leads to NAFLD and subsequent liver cancer. These effects were mediated through AKT/insulin signaling because co-deletion of both AKT phosphatase PTEN and SAV1 amplifies YAP/TAZ as well as AKT/IRS2. By contrast, pharmacological and genetic AKT/IRS2 as well as YAP/TAZ inhibition could prevent the development of liver tumors [23]. This YAP/insulin-signaling pathway interconnection is also observed in cardiomyocytes [74]. Upstream Hippo kinases also regulate liver metabolic functions, mostly independently of YAP, such as MST1 [18], MST3 [21], and LATS2 [20] in a Hippo non-canonical manner. MST3 is activated in the livers of high-fat diet (HFD)-induced obese mice. Liver-specific deletion of MST3 protects HFD-fed mice from the development of hyperglycemia, hyperinsulinemia, and insulin resistance. Analysis of cultured hepatic Pefloxacin Mesylate australia and the liver of mice fed with a HFD revealed that loss of MST3 enhances the insulin signaling pathway downstream of insulin receptor substrate 1 (IRS1). The activity of transcription factor forkhead box 1 (FOXO1), a key regulator of gluconeogenesis and glycogenolysis via insulin signaling 75, 76, together with gluconeogenic enzymes PCK1 and G6PC mRNAs, is reduced in MST3 knockout liver cells in vitro, leading to less glucose production, which is also in line with the effect of YAP to suppress PCK1 and G6PC [21]. A key advance in understanding the Hippo pathway in liver lipid metabolism came from a recent elegant study that shows its function in lipid synthesis 19, 20. LATS2 in cooperation with tumor-suppressor transcription factor p53 impairs sterol regulatory element binding proteins (SREBPs), master transcriptional regulators of lipogenesis, by disrupting endoplasmic reticulum (ER)-located SREBP1 and SREBP2 precursors. This leads to inhibition of the transcriptional activity of mature cleaved nuclear SREBPs (SREBPc) and the expression of lipogenic enzymes (Figure 3A). Loss of LATS2 thus induces SREBP activation, and mice with hepatocyte-specific deletion of LATS2 display excessive cholesterol synthesis and the development of steatosis and fatty liver disease [20]. Under non-physiological conditions of a high-cholesterol diet, LATS2 knockout mice develop severe liver damage, and induction of a p53-mediated proapoptotic response is compromised [20]. In this scenario, sustained induction of SREBP-c activity by loss of LATS2 under chronic metabolic stress leads to increased de novo lipogenesis and amplifies fat accumulation in the liver. Similarly, liver-specific MST1 deletion also results in enhanced lipid droplet accumulation, ballooning, and liver degeneration under non-physiological metabolic conditions, such as 48h fasting as well as during HFD feeding, which was mediated through an inverse MST1 effect on SREBP1c expression [18]. Mechanistically, MST1 stabilizes sirtuin 1 (SIRT1), an important regulator of hepatic glucose and lipid metabolism 77, 78 and negative regulator of SREBPs 79, 80 because fasting-induced expression of hepatic SIRT1 was abolished in MST1 knockout mice. Conversely, MST1 overexpression promotes SIRT1 stability by inhibiting SIRT1 ubiquitination [18]. Consistently, in a mouse model of YAP hyperactivation in liver by SAV1 deletion, SREBP1c protein expression was also highly upregulated [23]. This metabolic effect of Hippo kinases MST1 and LATS2 through a non-canonical Hippo pathway has direct implications for liver tumorigenesis because extensive alterations in lipid metabolism are evident during tumor growth. In humans, decreased LATS2 and increased SREBP were observed in advanced fatty liver disease [20], a severe state of liver steatosis with progressive increase in hepatic fat content, a hepatic manifestation of metabolic diseases such as T2D, and a major cause of liver cirrhosis and liver cancer [81]. These findings suggest that both Hippo core components LATS2 and MST1 (most likely through interplay with p53 19, 82 because both are obviously connected to p53 83, 84) act to control appropriate levels of SREBP activity for lipid homeostasis within the liver. This constitutes a metabolism-regulated network to maintain liver homeostasis.