Hepatocyte-specific IL11 cis-signaling drives lipotoxicity and underlies the transition from NAFLD to NASH

AbstractIL11 is important for fibrosis in non-alcoholic steatohepatitis (NASH) but its role beyond the stroma in liver disease is unclear. Here, we investigate the role of IL11 in hepatocyte lipotoxicity. Hepatocytes highly express IL11RA and secrete IL11 in response to lipid loading. Autocrine IL11 activity causes hepatocyte death through NOX4-derived ROS, activation of ERK, JNK and caspase-3, impaired mitochondrial function and reduced fatty acid oxidation. Paracrine IL11 activity stimulates hepatic stellate cells and causes fibrosis. In mouse models of NASH, hepatocyte-specific deletion of Il11ra1 protects against liver steatosis, fibrosis and inflammation while reducing serum glucose, cholesterol and triglyceride levels and limiting obesity. In mice deleted for Il11ra1, restoration of IL11 cis-signaling in hepatocytes reconstitutes steatosis and inflammation but not fibrosis. We found no evidence for the existence of IL6 or IL11 trans-signaling in hepatocytes or NASH. These data show that IL11 modulates hepatocyte metabolism and suggests a mechanism for NAFLD to NASH transition.

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The RNA-binding protein HuR promotes nonalcoholic steatohepatitis (NASH) progression by enhancing death signaling pathway

10.1101/2020.10.21.348185 ◽

2020 ◽

Author(s):

Xinzhi Li ◽

Bingchuan Yuan ◽

Zhicheng Yao ◽

Xu Sun ◽

Weixiang Guo ◽

...

Keyword(s):

Liver Injury ◽

Signaling Pathway ◽

Mrna Stability ◽

Caspase 3 ◽

Rna Binding ◽

Binding Protein ◽

Liver Steatosis ◽

Rna Binding Protein ◽

Hepatocyte Death ◽

Specific Deletion

AbstractHepatocyte death triggers liver inflammation, liver injury, and fibrosis, which contributes to non-alcoholic steatohepatitis (NASH) pathogenesis. However, whether RNA processing regulates death signaling pathway during NASH progression is not investigated. In this study, we show that HuR, a widely expressed RNA-binding protein, promotes NASH progression by increasing DR5/caspase8/caspase3-mediated hepatocyte death. Cytosolic HuR levels are abnormally elevated in human patients with NASH. Hepatocyte-specific deletion of HuR protects against MCD-induced NASH by decreasing liver steatosis, inflammation and cell death, whereas hepatic overexpression of HuR induces liver injury by increasing DR5-induced hepatocyte death. Furthermore, in primary hepatocytes, HuR deficiency ameliorates PA&TNFα-induced hepatocyte death due to decreased DR5/caspase8/caspase 3 signaling pathway while overexpression of HuR induces hepatocyte death by increasing DR5/caspase8/caspase 3 signaling pathway. Mechanistically, HuR directly binds to 3′-UTR of DR5 transcript and promotes its mRNA stability, contributing to the hepatocyte death during NASH progression. Our data reveal a novel mechanism by which HuR promotes mRNA stability of DR5, which contributes to NASH progression.

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Depdc5 deficiency exacerbates alcohol-induced hepatic steatosis via suppression of PPARα pathway

Cell Death and Disease ◽

10.1038/s41419-021-03980-6 ◽

2021 ◽

Vol 12 (7) ◽

Author(s):

Lin Xu ◽

Xinge Zhang ◽

Yue Xin ◽

Jie Ma ◽

Chenyan Yang ◽

...

Keyword(s):

Liver Injury ◽

Hepatic Steatosis ◽

Liver Steatosis ◽

Pharmacological Intervention ◽

Acid Oxidation ◽

Peroxisome Proliferator ◽

Pathological Effect ◽

Mtorc1 Pathway

AbstractAlcohol-related liver disease (ALD), a condition caused by alcohol overconsumption, occurs in three stages of liver injury including steatosis, hepatitis, and cirrhosis. DEP domain-containing protein 5 (DEPDC5), a component of GAP activities towards Rags 1 (GATOR1) complex, is a repressor of amino acid-sensing branch of the mammalian target of rapamycin complex 1 (mTORC1) pathway. In the current study, we found that aberrant activation of mTORC1 was likely attributed to the reduction of DEPDC5 in the livers of ethanol-fed mice or ALD patients. To further define the in vivo role of DEPDC5 in ALD development, we generated Depdc5 hepatocyte-specific knockout mouse model (Depdc5-LKO) in which mTORC1 pathway was constitutively activated through loss of the inhibitory effect of GATOR1. Hepatic Depdc5 ablation leads to mild hepatomegaly and liver injury and protects against diet-induced liver steatosis. In contrast, ethanol-fed Depdc5-LKO mice developed severe hepatic steatosis and inflammation. Pharmacological intervention with Torin 1 suppressed mTORC1 activity and remarkably ameliorated ethanol-induced hepatic steatosis and inflammation in both control and Depdc5-LKO mice. The pathological effect of sustained mTORC1 activity in ALD may be attributed to the suppression of peroxisome proliferator activated receptor α (PPARα), the master regulator of fatty acid oxidation in hepatocytes, because fenofibrate (PPARα agonist) treatment reverses ethanol-induced liver steatosis and inflammation in Depdc5-LKO mice. These findings provide novel insights into the in vivo role of hepatic DEPDC5 in the development of ALD.

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Hepatic stellate cells-specific Loxl1 deficiency abrogates hepatic inflammation, fibrosis, and corrects lipid metabolic abnormalities in non-obese NASH mice

10.21203/rs.3.rs-260786/v1 ◽

2021 ◽

Author(s):

Aiting Yang ◽

Xuzhen Yan ◽

Xu Fan ◽

Yiwen Shi ◽

Tao Huang ◽

...

Keyword(s):

Hepatic Stellate Cells ◽

Therapeutic Strategy ◽

Potential Role ◽

Lysyl Oxidase ◽

Control Diet ◽

Stellate Cells ◽

Metabolic Abnormalities ◽

Deficient Mice ◽

Specific Deletion

Abstract Background & Aims: Lysyl oxidase-like-1 (LOXL1), a vital crosslinking enzyme in extracellular matrix (ECM) protein maintenance, is well established in fibrosis via mediating ECM stabilization. However, the potential role of LOXL1 in the pathogenesis of nonalcoholic steatohepatitis (NASH) has not been previously studied.Methods: We generated Loxl1fl/fl mice to selectively delete Loxl1 in hepatic stellate cells (HSCs) (Loxl1fl/flGfapcre; Loxl1fl/fl as littermate controls) and then examined liver pathology and metabolic context in Loxl1fl/flGfapcre fed a choline-deficient L-amino acid-defined (CDAA) diet or an isocaloric control diet for 16 weeks. We confirmed study findings in 23 patients with biopsy-proven NAFLD.Results: LOXL1 was significantly increased in CDAA induced non-obese NASH compared with control diet. Here, utilizing a HSCs-specific deletion of Loxl1 model, we found that Loxl1 deficient in HSCs ameliorated CDAA-induced inflammation and fibrosis, with reduced expression of pro-inflammation and pro-fibrogenic genes. Interestingly, CDAA-fed Loxl1 deficient mice was associated with improved body weight and attenuated hepatic steatosis and to an up-regulation of leptin in adipose tissue and in serum, without changes in hepatic lipogenesis gene expression, compared with CDAA-fed control mice. Most importantly, analyses of serum LOXL1 and leptin levels from NAFLD patients revealed that LOXL1 was positively correlated with histological fibrosis progression, whereas was inversely correlated with leptin levels, especially in non-obese NAFLD patients.Conclusion: In a mouse model of CDAA-induced non-obese NASH, selective deletion of Loxl1 from HSCs attenuated steatohepatitis, hepatic fibrosis and improved lipid metabolic abnormalities. Hence, LOXL1 inhibition may serve as a new therapeutic strategy for NASH.

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Involvement of Rho/Rho kinase pathway in regulation of apoptosis in rat hepatic stellate cells

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00039.2003 ◽

2003 ◽

Vol 285 (5) ◽

pp. G880-G886 ◽

Cited By ~ 49

Author(s):

Hitoshi Ikeda ◽

Kayo Nagashima ◽

Mikio Yanase ◽

Tomoaki Tomiya ◽

Masahiro Arai ◽

...

Keyword(s):

Dna Fragmentation ◽

Hepatic Fibrosis ◽

Lysophosphatidic Acid ◽

Hepatic Stellate Cells ◽

Therapeutic Strategy ◽

Caspase 3 ◽

Rho Kinase ◽

Stellate Cells ◽

Kinase Pathway

Hepatic stellate cells (HSCs) play a central role in the development of hepatic fibrosis. Recent evidence has revealed that HSCs also play a role in its resolution, where HSC apoptosis was determined. Moreover, induction of HSC apoptosis caused a reduction of experimental hepatic fibrosis in rats. Thus knowing the mechanism of HSC apoptosis might be important to clarify the pathophysiology and establish the therapeutic strategy for hepatic fibrosis. In HSCs, Rho and Rho kinase are known to regulate contraction, migration, and proliferation with modulation of cell morphology. Controversy exists as to the participation of Rho and Rho kinase on cell survival, and little is known regarding this matter in HSCs. In this study, we directed our focus on the role of the Rho pathway in the regulation of HSC survival. C3, an inhibitor of Rho, increased histone-associated DNA fragmentation and caspase 3 activity with enhanced condensation of nuclear chromatin in rat cultured HSCs. Moreover, Y-27632, an inhibitor of Rho kinase, had the same effects, suggesting that inhibition of the Rho/Rho kinase pathway causes HSC apoptosis. On the other hand, lysophosphatidic acid, which stimulates the Rho/Rho kinase pathway, decreased histone-associated DNA fragmentation in HSCs. Inhibition of the Rho/Rho kinase pathway did not affect p53, Bcl-2, or Bax levels in HSCs. Thus we concluded that the Rho/Rho kinase pathway may play a role in the regulation of HSC survival.

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Non-apoptotic function of caspase-3 in morphogenesis of epithelial tubes of Drosophila renal system

10.1101/2020.08.17.219634 ◽

2020 ◽

Author(s):

Shainy Ojha ◽

Madhu G. Tapadia

Keyword(s):

Caspase 3 ◽

Stellate Cells ◽

Probable Mechanism ◽

Malpighian Tubules ◽

Fine Tuning ◽

Convergent Extension ◽

Cytoskeleton Organization ◽

Cell Mobility ◽

And Function

AbstractCells trigger apoptosis to eliminate themselves from the system, when tissue needs to be sculptured or they detect any abnormality within them, thus preventing irreparable damage to the host. Drosophila Malpighian tubules express apoptotic proteins, without succumbing to cell death. Here we present evidence to show apoptosis independent role of executioner caspase, Drice, for precise architecture and function of Malpighian tubules. Drice is required for precise cytoskeleton organization and convergent extension, failing which the morphology, size, cellular number and arrangement gets affected. Acquisition of star shape of stellate cells in adult Malpighian tubules requires Drice. We demonstrate that Drice regulates expression of Rho1GTPase and localization of polarity proteins. Our study shows a probable mechanism by which Drice governs tubulogenesis via Rho1GTPase mediated coordinated organization of actin cytoskeleton and membrane stablisation. Furthermore, defective morphology of tubules leads to abnormal osmoregulation and excretory functions. Collectively our findings suggest a possible non-apoptotic function of caspase-3 in the fine tuning of cell mobility during tubule development and our results will add to the growing understanding of diverse roles of caspases during its evolution in metazoans.

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Autocrine IL11 cis-signaling in hepatocytes is an initiating nexus between lipotoxicity and non-alcoholic steatohepatitis

10.1101/2020.03.11.986802 ◽

2020 ◽

Author(s):

Jinrui Dong ◽

Eleonora Adami ◽

Sonia P. Chothani ◽

Sivakumar Viswanathan ◽

Benjamin Ng ◽

...

Keyword(s):

Preclinical Models ◽

Disease Mechanism ◽

Serum Samples ◽

Deficient Diet ◽

Beneficial Effects ◽

Alcoholic Steatohepatitis ◽

Hepatocyte Death ◽

Specific Deletion

AbstractBackground and aimsIL11 signaling is important in non-alcoholic steatohepatitis (NASH) but how it contributes to NASH pathologies beyond fibrosis is not known. Here we investigate the role of IL11 signaling in hepatocyte lipotoxicity.MethodsHepatocytes were stimulated with IL6, IL11, HyperIL6, or HyperIL11 alone or in the presence of soluble gp130 (sgp130) or soluble IL11RA (sIL11RA), or loaded with palmitate in the presence of IgG or anti-IL11RA (X209) antibodies or sgp130. Effects were assessed using colorimetric ALT, GSH, or ELISA assays, immunoblots, and flow cytometry. The relative contributions of IL11 cis-versus -trans signaling in vivo was assessed in two preclinical NASH models using a high fat methionine/choline deficient diet or a Western diet with liquid fructose in C57BL6/Ntac mice injected with AAV8-Alb-Cre, AAV8-Alb-sgp130, in mice with hepatocyte-specific deletion of Il11ra (CKO), and in mice with global deletion of Il11ra injected with AAV8-Alb-mIl11ra or AAV8-Alb-sIl11ra. Livers and serum were collected; serum samples were analyzed using biochemistry and liver tissues were analyzed by histology, qPCR, immunobloting, hydroxyproline, and GSH assays.ResultsWe show that lipid-laden hepatocytes secrete IL11, which acts via autocrine cis-signaling to cause lipoapoptosis. IL11 causes lipotoxic hepatocyte death through activation of non-canonical signaling pathways and increased NOX4-derived reactive oxygen species. In two preclinical models, hepatocyte-specific deletion of Il11ra1 protects mice from all aspects of NASH with beneficial effects on body weight. In accordance, restoration of IL11 cis-signaling in hepatocytes only in mice globally deleted for Il11ra1 reconstitutes steatosis and inflammation. Throughout, we found no evidence to support the existence of IL6 or IL11 trans-signaling in the liver.ConclusionWe conclude that autocrine IL11-mediated cell death underlies hepatocyte lipotoxicity and that liver fibrosis and inflammation occur subsequently. These data highlight a new disease mechanism for the transition from compensated fatty liver disease to NASH.

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