Obeticholic acid protects against carbon tetrachloride-induced acute liver injury and inflammation

Zhang, Da-Gang; Zhang, Cheng; Wang, Junxian; Wang, Bi-Wei; Wang, Hua; Zhang, Zhihui; Chen, Yuan-Hua; Lü, Yan; Li, Tao; Wang, Jianqing; Chen, Xi; D, Xu

doi:10.1016/j.taap.2016.11.006

Cited by 66 publications

(40 citation statements)

References 57 publications

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“…We show that OCA quantitatively reduces hepatic fibrosis as measured by traditional picrosirius red staining, as well as biochemically measured collagen levels. This is in line with the findings of others, who report reduced hepatic collagen content after OCA treatment in chemically induced liver fibrosis and in AMLN diet (high trans‐fat and fructose diet supplemented with 2% cholesterol)–fed ob/ob mice . In addition to the observed reduction in the level of collagen in the liver in the present study, OCA also lowered the degree of reticulation of collagen (of both thin and aggregated collagen fibers) as assessed by multiphoton imaging, a technology that allows the dissection of fibrosis stages in human biopsies .…”

Section: Discussionsupporting

confidence: 93%

“…Considerable efforts are being made to develop pharmacological therapies that normalize the metabolic‐inflammatory disturbances in the liver and thereby attenuate the development of NASH and fibrosis . The farnesoid X receptor (FXR) agonist obeticholic acid (OCA) is one of the most promising candidate drugs, based on preclinical studies in acute models of inflammation and fibrosis as well as on published results from clinical studies . However, the mechanisms by which OCA can attenuate metabolically induced inflammation and associated pathways leading to fibrosis remain largely unknown.…”

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confidence: 99%

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Obeticholic Acid Modulates Serum Metabolites and Gene Signatures Characteristic of Human NASH and Attenuates Inflammation and Fibrosis Progression in Ldlr‐/‐.Leiden Mice

et al. 2018

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Concerns have been raised about whether preclinical models sufficiently mimic molecular disease processes observed in nonalcoholic steatohepatitis (NASH) patients, bringing into question their translational value in studies of therapeutic interventions in the process of NASH/fibrosis. We investigated the representation of molecular disease patterns characteristic for human NASH in high‐fat diet (HFD)‐fed Ldlr‐/‐.Leiden mice and studied the effects of obeticholic acid (OCA) on these disease profiles. Multiplatform serum metabolomic profiles and genome‐wide liver transcriptome from HFD‐fed Ldlr‐/‐.Leiden mice were compared with those of NASH patients. Mice were profiled at the stage of mild (24 weeks HFD) and severe (34 weeks HFD) fibrosis, and after OCA intervention (24‐34 weeks; 10 mg/kg/day). Effects of OCA were analyzed histologically, biochemically, by immunohistochemistry, using deuterated water technology (de novo collagen formation), and by its effect on the human‐based transcriptomics and metabolomics signatures. The transcriptomics and metabolomics profile of Ldlr‐/‐.Leiden mice largely reflected the molecular signature of NASH patients. OCA modulated the expression of these molecular profiles and quenched specific proinflammatory‐profibrotic pathways. OCA attenuated specific facets of cellular inflammation in liver (F4/80‐positive cells) and reduced crown‐like structures in adipose tissue. OCA reduced de novo collagen formation and attenuated further progression of liver fibrosis, but did not reduce fibrosis below the level before intervention. Conclusion: HFD‐fed Ldlr‐/‐.Leiden mice recapitulate molecular transcriptomic and metabolomic profiles of NASH patients, and these signatures are modulated by OCA. Intervention with OCA in developing fibrosis reduces collagen deposition and de novo synthesis but does not resolve already manifest fibrosis in the period studied. These data show that human molecular signatures can be used to evaluate the translational character of preclinical models for NASH.

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Section: Discussionsupporting

confidence: 93%

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confidence: 99%

Obeticholic Acid Modulates Serum Metabolites and Gene Signatures Characteristic of Human NASH and Attenuates Inflammation and Fibrosis Progression in Ldlr‐/‐.Leiden Mice

et al. 2018

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“…However, the underlying mechanism is poorly investigated. Previous studies reported that CCl 4 -induced hepatocyte apoptosis through ER stress pathway in vivo and in vitro Lee et al, 2016;San-Miguel et al, 2015;D. G. Zhang et al, 2017), while there is no study concerning the role of MFGE8 in regulating ER stress pathway.…”

Section: Discussionmentioning

confidence: 98%

MFGE8 protects against CCl₄‐induced liver injury by reducing apoptosis and promoting proliferation of hepatocytes

Zhang

Wang

et al. 2019

Journal Cellular Physiology

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Milk fat globule‐EGF factor 8 (MFGE8) has been reported to play various roles in acute injury and inflammation response. However, the role of MFGE8 in liver injury is poorly investigated. The present research was designed to clarify the expression and function of MFGE8 in carbon tetrachloride (CCl4)‐induced liver injury. Using serum cytokine arrays, we selected a promising cytokine MFGE8 as the candidate in the process of hepatitis‐fibrosis‐hepatocellular carcinoma (HCC) progression, based on the elevated expression in both hepatic fibrosis and HCC models. We validated the increased expression of MFGE8 in liver tissues and serum samples of acute and chronic CCl4‐induced mice. Immunohistochemistry staining of mouse liver tissues indicated that elevated MFGE8 expression was mainly derived from the injured hepatocytes. In addition, MFGE8 expression in the supernatant of primary hepatocytes was accumulated with prolongation of culture time, and CCl4 treatment further increased the expression of MFGE8. Moreover, a strong correlation between serum MFGE8 expression and liver transaminase activities suggested that MFGE8 may be a novel candidate in liver injury. Intriguingly, mice pretreated with MFGE8 were protected from CCl4‐induced liver injury through antiapoptosis role in the early stage and proproliferation role in the late stage. MFGE8 reduced apoptosis by inhibiting the activation of IRE1α/ASK1/JNK pathway and promoted proliferation by phosphorylation of ERK and AKT. Moreover, serum MFGE8 expression was increased in hepatitis patients while decreased in liver cirrhosis patients. All the results suggest MFGE8 as a novel marker and promising therapeutic agent of liver injury.

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“…Several cellular and molecular cascades of events, including oxidative stress, inflammation, hepatocyte apoptosis and necrosis, immune responses, etc. have been considered to contribute to the pathogenesis and progression of this disorder [ 13 , 14 ]. It is well-known that carbon tetrachloride (CCl 4 )-induced acute liver injury model shares a similar molecular mechanism with acute chemical liver injury in humans [ 15 ].…”

Section: Introductionmentioning

confidence: 99%

Protective Effect of Eckol against Acute Hepatic Injury Induced by Carbon Tetrachloride in Mice

Liu

Zhang

et al. 2018

Marine Drugs

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Several in vitro studies have shown the potential hepatoprotective properties of eckol, a natural phlorotannin derived from the brown alga. However, the in vivo hepatoprotective potential of eckol has not been determined. In this study, we performed an in vivo study to investigate the protective effect of eckol and its possible mechanisms on the carbon tetrachloride (CCl4)-induced acute liver injury model in mice. Results revealed that eckol pre-treatment at the dose of 0.5 and 1.0 mg/kg/day for 7 days significantly suppressed the CCl4-induced increases of alanine transaminase (ALT) and aspartate aminotransferase (AST) levels in serum and meliorated morphological liver injury. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling (TUNEL) analysis showed that the number of positive apoptotic hepatocytes in the eckol-treated group was lower than that in the CCl4 model group. Western blotting analysis also demonstrated the enhanced expression of bcl-2 and suppressed expression of cleaved caspase-3 by eckol. The CCl4-induced oxidative stress in liver was significantly ameliorated by eckol, which was characterized by reduced malondialdehyde (MDA) formations, and enhanced superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) activities and glutathione (GSH) content. Moreover, the CCl4-induced elevations of pro-inflammatory cytokines tumor necrosis factor (TNF)-α, interleukin (IL)-1β and IL-6 were markedly suppressed in the eckol-treated group. However, eckol enhanced the level of IL-10, a potent anti-inflammatory cytokine, and recruited CD11c+ dendritic cells into the liver tissues of CCl4-treated mice. These results indicated that eckol has the protective effect on CCl4-induced acute liver injury via multiple mechanisms including anti-apoptosis, anti-oxidation, anti-inflammation and immune regulation.

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Obeticholic acid protects against carbon tetrachloride-induced acute liver injury and inflammation

Cited by 66 publications

References 57 publications

Obeticholic Acid Modulates Serum Metabolites and Gene Signatures Characteristic of Human NASH and Attenuates Inflammation and Fibrosis Progression in Ldlr‐/‐.Leiden Mice

Obeticholic Acid Modulates Serum Metabolites and Gene Signatures Characteristic of Human NASH and Attenuates Inflammation and Fibrosis Progression in Ldlr‐/‐.Leiden Mice

MFGE8 protects against CCl₄‐induced liver injury by reducing apoptosis and promoting proliferation of hepatocytes

Protective Effect of Eckol against Acute Hepatic Injury Induced by Carbon Tetrachloride in Mice

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Obeticholic acid protects against carbon tetrachloride-induced acute liver injury and inflammation

Cited by 66 publications

References 57 publications

Obeticholic Acid Modulates Serum Metabolites and Gene Signatures Characteristic of Human NASH and Attenuates Inflammation and Fibrosis Progression in Ldlr‐/‐.Leiden Mice

Obeticholic Acid Modulates Serum Metabolites and Gene Signatures Characteristic of Human NASH and Attenuates Inflammation and Fibrosis Progression in Ldlr‐/‐.Leiden Mice

MFGE8 protects against CCl4‐induced liver injury by reducing apoptosis and promoting proliferation of hepatocytes

Protective Effect of Eckol against Acute Hepatic Injury Induced by Carbon Tetrachloride in Mice

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MFGE8 protects against CCl₄‐induced liver injury by reducing apoptosis and promoting proliferation of hepatocytes