Hepatic stellate cells as key target in liver fibrosis

Higashi, Taishi; Friedman, Scott L.; Hoshida, Yujin

doi:10.1016/j.addr.2017.05.007

Cited by 1,040 publications

(978 citation statements)

References 334 publications

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“…Ongoing hepatocyte injury and inflammation result in uncontrolled activation and proliferation of hepatic stellate cells (HSCs) and the development of fibrosis and cirrhosis [98–100]. Liver fibrosis occurs in multiple types of chronic liver injury, and unfortunately, there is no FDA-approved specific therapy for fibrosis.…”

Section: The Role Of Camp In Nafldmentioning

confidence: 99%

Role of cAMP and phosphodiesterase signaling in liver health and disease

Wahlang

McClain

Barve

et al. 2018

Cellular Signalling

103

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Liver disease is a significant health problem worldwide with mortality reaching around 2 million deaths a year. Non-alcoholic fatty liver disease (NAFLD) and alcoholic liver disease (ALD) are the major causes of chronic liver disease. Pathologically, NAFLD and ALD share similar patterns of hepatic disorders ranging from simple steatosis to steatohepatitis, fibrosis and cirrhosis. It is becoming increasingly important to identify new pharmacological targets, given that there is no FDA-approved therapy yet for either NAFLD or ALD. Since the evolution of liver diseases is a multifactorial process, several mechanisms involving parenchymal and non-parenchymal hepatic cells contribute to the initiation and progression of liver pathologies. Moreover, certain protective molecular pathways become repressed during liver injury including signaling pathways such as the cyclic adenosine monophosphate (cAMP) pathway. cAMP, a key second messenger molecule, regulates various cellular functions including lipid metabolism, inflammation, cell differentiation and injury by affecting gene/protein expression and function. This review addresses the current understanding of the role of cAMP metabolism and consequent cAMP signaling pathway(s) in the context of liver health and disease. The cAMP pathway is extremely sophisticated and complex with specific cellular functions dictated by numerous factors such abundance, localization and degradation by phosphodiesterases (PDEs). Furthermore, because of the distinct yet divergent roles of both of its effector molecules, the cAMP pathway is extensively targeted in liver injury to modify its role from physiological to therapeutic, depending on the hepatic condition. This review also examines the behavior of the cAMP-dependent pathway in NAFLD, ALD and in other liver diseases and focuses on PDE inhibition as an excellent therapeutic target in these conditions.

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Section: The Role Of Camp In Nafldmentioning

confidence: 99%

Role of cAMP and phosphodiesterase signaling in liver health and disease

Wahlang

McClain

Barve

et al. 2018

Cellular Signalling

103

View full text Add to dashboard Cite

show abstract

“…Fibrosis is a consequence of chronic injury associated with alcoholic liver disease (ALD), non-alcoholic fatty liver disease (NAFLD) as well as chronic viral diseases such as hepatitis C viral infection [3,4]. Hepatic stellate cells (HSCs) are the primary players in hepatic fibrosis development and progression [5].…”

Section: Introductionmentioning

confidence: 99%

Adiponectin inhibits hepatic stellate cell activation by targeting the PTEN/AKT pathway

Kumar¹,

Raeman²,

Chopyk³

et al. 2018

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Adiponectin inhibits hepatic stellate cell (HSC) activation and subsequent development of liver fibrosis via multiple mechanisms. Phosphatase and tensin homolog deletion 10 (PTEN) plays a crucial role in suppression of HSC activation, but its regulation by adiponectin is not fully understood. Here, we investigated the effect of adiponectin on PTEN in LX-2 cells, a human cell line and examined the underlying molecular mechanisms involved in adiponectin-mediated upregulation of PTEN activity during fibrosis. PTEN expression was found to be significantly reduced in the livers of mice treated with CCl4, whereas its expression was rescued by adiponectin treatment. The DNA methylation proteins DNMT1, DNMT3A, and DNMT3B are all highly expressed in activated primary HSCs compared to quiescent HSCs, and thus represent additional regulatory targets during liver fibrogenesis. Expression of DNMT proteins was significantly induced in the presence of fibrotic stimuli; however, only DNMT3B expression was reduced in the presence of adiponectin. Adiponectin-induced suppression of DNMT3B was found to be mediated by enhanced miR-29b expression. Furthermore, PTEN expression was significantly increased by overexpression of miR-29b, whereas its expression was markedly reduced by a miR-29b inhibitor in LX-2 cells. These findings suggest that adiponectin-induced upregulation of miR-29b can suppress DNMT3B transcription in LX-2 cells, thus resulting in reduced methylation of PTEN CpG islands and ultimately suppressing the PI3K/AKT pathway. Together, these data suggest a possible new explanation for the inhibitory effect of adiponectin on HSC activation and liver fibrogenesis.

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“…Liver fibrosis and cirrhosis are mainly caused by chronic liver disease, which has become a worldwide issue. The main pathological feature of liver fibrosis is the accumulation of extracellular matrix (ECM), mainly collagen, secreted by myofibroblast‐like hepatic stellate cells (HSCs) in damaged liver . Currently there are still no satisfactory anti‐fibrosis therapeutics for clinical treatment due to the low drug efficacy caused by poor liver targeting and short half‐life, and the toxic side effects caused by the drug accumulation in other tissues.…”

Section: Introductionmentioning

confidence: 99%

“…Hepatic stellate cells are activated from quiescent status and secreted ECM protein in liver fibrosis . Apoptosis of activated HSCs (aHSCs) is an important mechanism for liver fibrosis recovery.…”

Section: Introductionmentioning

confidence: 99%

Chemically modified liposomes carrying TRAIL target activated hepatic stellate cells and ameliorate hepatic fibrosis in vitro and in vivo

Ding

Guo

et al. 2018

J Cellular Molecular Medi

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At present, no satisfactory anti‐liver fibrosis drugs have been used clinically due to the poor targeting ability and short half‐life period. This study aimed to explore the effects of a new TRAIL ( TNF ‐related apoptosis‐inducing ligand) preparation that can target aHSC s (activated hepatic stellate cells) on liver fibrosis and explain the possible underlying mechanism. Using our self‐made drug carrier pPB ‐ SSL that specifically targets aHSC s, recombinant human TRAIL (rh TRAIL ) protein was embedded in (named as pPB ‐ SSL ‐ TRAIL ) and applied to treat liver fibrotic mice as well as 3T3 fibroblast cells and aHSC s. Through in vitro and in vivo experiments, we found that, compared with the groups treated with TRAIL (free rh TRAIL ) and SSL ‐ TRAIL (rh TRAIL capsulated within unmodified liposome), the group treated with pPB ‐ SSL ‐ TRAIL nanoparticles showed significantly lower cell viability and higher cell apoptosis in vitro. The targeting delivering system pPB ‐ SSL also significantly enhanced the anti‐fibrotic effect, apoptosis induction and long circulation of rh TRAIL . After the treatment with pPB ‐ SSL ‐ TRAIL , apoptosis of aHSC s was notably increased and hepatic fibrosis in mice was remarkably alleviated. In vitro, pPB ‐ SSL ‐ TRAIL nanoparticles were mainly transported and located on membrane or into cytoplasm, but the particles were distributed mainly in mouse fibrotic liver and most on the cell membrane of aHSC s. In conclusion, rh TRAIL carried by pPB ‐ SSL delivering system has prolonged circulation in blood, be able to target aHSC s specifically, and alleviate fibrosis both in vitro and in vivo. It presents promising prospect in the therapy of liver fibrosis, and it is worthwhile for us to develop it for clinical use.

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Hepatic stellate cells as key target in liver fibrosis

Cited by 1,040 publications

References 334 publications

Role of cAMP and phosphodiesterase signaling in liver health and disease

Role of cAMP and phosphodiesterase signaling in liver health and disease

Adiponectin inhibits hepatic stellate cell activation by targeting the PTEN/AKT pathway

Chemically modified liposomes carrying TRAIL target activated hepatic stellate cells and ameliorate hepatic fibrosis in vitro and in vivo

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