Hepatocytic p62 suppresses ductular reaction and tumorigenesis in mouse livers with mTORC1 activation and defective autophagy

AbstractAlcohol Use Disorder (AUD) affects a large portion of the population. Unfortunately, efficacious medications to treat the disease are limited. Studies in rodents suggest that mTORC1 plays a crucial role in mechanisms underlying phenotypes such as heavy alcohol intake, habit, and relapse. Thus, mTORC1 inhibitors, which are used in the clinic, are promising therapeutic agents to treat AUD. However, chronic inhibition of mTORC1 in the periphery produces undesirable side effects, which limit their potential use for the treatment of AUD. To overcome these limitations, we designed a binary drug strategy in which male mice were treated with the mTORC1 inhibitor RapaLink-1 together with a small molecule (RapaBlock) to protect mTORC1 activity in the periphery. We show that whereas RapaLink-1 administration blocked mTORC1 activation in the liver, RapaBlock abolished the inhibitory action of Rapalink-1. RapaBlock also prevented the adverse side effects produced by chronic inhibition of mTORC1. Importantly, co-administration of RapaLink-1 and RapaBlock inhibited alcohol-dependent mTORC1 activation in the nucleus accumbens and attenuated alcohol seeking and drinking.

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Keratin 7 expression in hepatic cholestatic diseases

Virchows Archiv ◽

10.1007/s00428-021-03152-z ◽

2021 ◽

Author(s):

S. Sakellariou ◽

C. Michaelides ◽

T. Voulgaris ◽

J. Vlachogiannakos ◽

E. Manesis ◽

...

Keyword(s):

Bile Duct ◽

Inverse Correlation ◽

Bile Duct Obstruction ◽

Hepatocyte Proliferation ◽

Primary Biliary Cholangitis ◽

Specific Marker ◽

Ductular Reaction ◽

Duct Obstruction ◽

Cholestatic Diseases ◽

Keratin 7

AbstractWe evaluated keratin 7 (K7) hepatocellular expression in 92 patients with common types of acute and chronic cholestatic diseases caused by bile duct obstruction/destruction or parenchymal lesions [acute hepatitis (n=20), mixed/pure cholestasis (n=16), primary biliary cholangitis-PBC (n=35), primary sclerosing cholangitis-PSC (n=10), vanishing bile duct syndrome (n=3), complete large bile duct obstruction due to space-occupying lesions (n=8)]. K7 immunohistochemical hepatocellular expression and ductular reaction (DR) were semi-quantitatively assessed. Results were correlated with liver enzyme serum levels, cholestasis type, histological features, hepatocellular Ki67 labelling index (LI) and HepPar1 expression. Hepatocellular K7 expression was detected in 87% (81/92) cases and in all cholestatic disease types with lowest incidence in pure/mixed cholestasis and highest in incomplete bile duct obstruction (iBDO), reaching 100% in PSC. K7-positive hepatocytes had low Ki67 LI (0-5%) retaining HepPar1 expression, irrespective of disease type. PSC cases had high K7 hepatocellular expression even with intact bile ducts, a feature that may aid differential diagnosis of cholestatic syndromes. K7 hepatocellular expression significantly correlated with cholestasis type, bile duct loss and fibrosis stage. It was higher in milder acute cholestatic hepatitis showing inverse correlation with hepatocyte proliferation and serum transaminase levels. In iBDO, younger age independently correlated with high K7 expression, while serum GGT levels showed a nearly significant correlation. Correlation with DR findings implied that K7-positive hepatocytes may result through metaplasia. In conclusion, K7 hepatocellular expression is a sensitive though non-specific marker of cholestasis. It may represent a cytoprotective reaction of resting hepatocytes in cholestasis of longer duration especially in younger patients.

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Leucine-sensing mechanism of leucyl-tRNA synthetase 1 for mTORC1 activation

Cell Reports ◽

10.1016/j.celrep.2021.109031 ◽

2021 ◽

Vol 35 (4) ◽

pp. 109031

Author(s):

Sulhee Kim ◽

Ina Yoon ◽

Jonghyeon Son ◽

Junga Park ◽

Kibum Kim ◽

...

Keyword(s):

Trna Synthetase ◽

Sensing Mechanism ◽

Mtorc1 Activation

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The complex network of mTOR signalling in the heart

Cardiovascular Research ◽

10.1093/cvr/cvab033 ◽

2021 ◽

Author(s):

Sebastiano Sciarretta ◽

Maurizio Forte ◽

Giacomo Frati ◽

Junichi Sadoshima

Keyword(s):

Cardiovascular System ◽

Cardiac Development ◽

Metabolic Stress ◽

Pressure Overload ◽

Current Data ◽

Loss Of Function ◽

Extracellular Signals ◽

Mtorc1 Activation ◽

Mtor Modulation ◽

Mtor Signalling

Abstract The mechanistic target of rapamycin (mTOR) integrates several intracellular and extracellular signals involved in the regulation of anabolic and catabolic processes. mTOR assembles into two macromolecular complexes, named mTORC1 and mTORC2, which have different regulators, substrates and functions. Studies of gain- and loss-of-function animal models of mTOR signalling revealed that mTORC1/2 elicits both adaptive and maladaptive functions in the cardiovascular system. Both mTORC1 and mTORC2 are indispensable for driving cardiac development and cardiac adaption to stress, such as pressure overload. However, persistent and deregulated mTORC1 activation in the heart is detrimental during stress and contributes to the development and progression of cardiac remodelling and genetic and metabolic cardiomyopathies. In this review, we discuss the latest findings regarding the role of mTOR in the cardiovascular system, both under basal conditions and during stress, such as pressure overload, ischemia, and metabolic stress. Current data suggest that mTOR modulation may represent a potential therapeutic strategy for the treatment of cardiac diseases.

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Cytokeratin19 positive hepatocellular carcinoma is associated with increased peritumoral ductular reaction

Annals of Hepatology ◽

10.5604/16652681.1198813 ◽

2016 ◽

Vol 15 (3) ◽

pp. 386-393

Author(s):

Xiaobo Cai ◽

Li Feng ◽

Heng Liu ◽

Mingyi Xu ◽

Yin Qu ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Ductular Reaction

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Prostaglandin E2 activates the mTORC1 pathway through an EP4/cAMP/PKA- and EP1/Ca2+-mediated mechanism in the human pancreatic carcinoma cell line PANC-1

AJP Cell Physiology ◽

10.1152/ajpcell.00417.2014 ◽

2015 ◽

Vol 309 (10) ◽

pp. C639-C649 ◽

Cited By ~ 17

Author(s):

Hui-Hua Chang ◽

Steven H. Young ◽

James Sinnett-Smith ◽

Caroline Ei Ne Chou ◽

Aune Moro ◽

...

Keyword(s):

Insulin Resistance ◽

Pancreatic Cancer ◽

Prostaglandin E2 ◽

Human Pancreatic Cancer ◽

Pancreatic Carcinoma Cell Line ◽

Pancreatic Cancer Cells ◽

Mtorc1 Signaling ◽

Mtorc1 Pathway ◽

Pka Pathway ◽

Mtorc1 Activation

Obesity, a known risk factor for pancreatic cancer, is associated with inflammation and insulin resistance. Proinflammatory prostaglandin E2 (PGE2) and elevated insulin-like growth factor type 1 (IGF-1), related to insulin resistance, are shown to play critical roles in pancreatic cancer progression. We aimed to explore a potential cross talk between PGE2 signaling and the IGF-1/Akt/mammalian target of rapamycin complex 1 (mTORC1) pathway in pancreatic cancer, which may be a key to unraveling the obesity-cancer link. In PANC-1 human pancreatic cancer cells, we showed that PGE2 stimulated mTORC1 activity independently of Akt, as evaluated by downstream signaling events. Subsequently, using pharmacological and genetic approaches, we demonstrated that PGE2-induced mTORC1 activation is mediated by the EP4/cAMP/PKA pathway, as well as an EP1/Ca2+-dependent pathway. The cooperative roles of the two pathways were supported by the maximal inhibition achieved with the combined pharmacological blockade, and the coexistence of highly expressed EP1 (mediating the Ca2+ response) and EP2 or EP4 (mediating the cAMP/PKA pathway) in PANC-1 cells and in the prostate cancer line PC-3, which also robustly exhibited PGE2-induced mTORC1 activation, as identified from a screen in various cancer cell lines. Importantly, we showed a reinforcing interaction between PGE2 and IGF-1 on mTORC1 signaling, with an increase in IL-23 production as a cellular outcome. Our data reveal a previously unrecognized mechanism of PGE2-stimulated mTORC1 activation mediated by EP4/cAMP/PKA and EP1/Ca2+ signaling, which may be of great importance in elucidating the promoting effects of obesity in pancreatic cancer. Ultimately, a precise understanding of these molecular links may provide novel targets for efficacious interventions devoid of adverse effects.

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