Fibrosis is the major determinant of morbidity and mortality in patients with nonalcoholic steatohepatitis (NASH) but has no approved pharmacotherapy in part because of incomplete understanding of its pathogenic mechanisms. Here, we report that hepatocyte Notch activity tracks with disease severity and treatment response in patients with NASH and is similarly increased in a mouse model of diet-induced NASH and liver fibrosis. Hepatocyte-specific Notch loss-of-function mouse models showed attenuated NASH-associated liver fibrosis, demonstrating causality to obesity-induced liver pathology. Conversely, forced activation of hepatocyte Notch induced fibrosis in both chow- and NASH diet–fed mice by increasing Sox9-dependent Osteopontin (Opn) expression and secretion from hepatocytes, which activate resident hepatic stellate cells. In a cross-sectional study, we found that OPN explains the positive correlation between liver Notch activity and fibrosis stage in patients. Further, we developed a Notch inhibitor [Nicastrin antisense oligonucleotide (Ncst ASO)] that reduced fibrosis in NASH diet–fed mice. In summary, these studies demonstrate the pathological role and therapeutic accessibility of the maladaptive hepatocyte Notch response in NASH-associated liver fibrosis.

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This paper investigates a cooperative nonorthogonal multiple access (NOMA) system, in which a base station communicates with two far users with the aid of a decode-and-forward (DF) relay. Three cooperative relaying schemes, namely, the fixed relaying (FR), selective DF with coordinated direct and relay transmission (SDF-CDRT), and incremental-selective DF (ISDF) relaying are proposed to enhance the outage performance for the two far users by utilizing both the direct and relay links. Taking into account the received signal-to-noise ratio (SNR) events at the relay, the SDF-CDRT scheme adaptively forms an orthogonal transmission branch with respect to the direct link or keeps silent to reduce error propagation. Besides considering the relay detection results, the ISDF scheme further exploits the limited feedback of the received SNR events from two users, so that error propagation can be avoided and unnecessary relaying can be reduced. Analytical expressions for the outage probabilities and average throughputs of the paired users are derived in the closed-form for the three cooperative relaying schemes. Asymptotic expressions for the outage probabilities are derived in the high SNR region. It is shown that the FR and SDF-CDRT schemes achieve a diversity order of one for both users, while the ISDF scheme achieves a diversity order of two for both users. The superior system performance achieved by the proposed schemes over those of the existing methods is verified by Monte Carlo simulations.

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Mechanistic target of rapamycin complex 1 (mTORC1), defined by the presence of Raptor, is an evolutionarily conserved and nutrient-sensitive regulator of cellular growth and other metabolic processes. To date, all known functions of Raptor involve its scaffolding mTOR kinase with substrate. Here we report that mTORC1-independent (‘free') Raptor negatively regulates hepatic Akt activity and lipogenesis. Free Raptor levels in liver decline with age and in obesity; restoration of free Raptor levels reduces liver triglyceride content, through reduced β-TrCP-mediated degradation of the Akt phosphatase, PHLPP2. Commensurately, forced PHLPP2 expression ameliorates hepatic steatosis in diet-induced obese mice. These data suggest that the balance of free and mTORC1-associated Raptor governs hepatic lipid accumulation, and uncover the potentially therapeutic role of PHLPP2 activators in non-alcoholic fatty liver disease.