Thiazolidinediones and hepatic fibrosis: don't wait too long

Marra, Fabio

doi:10.1136/gut.2005.085399

Cited by 10 publications

(5 citation statements)

References 27 publications

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“…Importantly, treatment of experimentally-induced fibrosis with PPARγ ligands prevented hepatic fibrosis in some in vivo models[ 19 - 21 ]. However, recent studies have suggested that TZD treatment may be ineffective for established fibrosis in rodents, casting some doubt on the utility of using TZDs alone for this purpose[ 22 - 24 ].…”

Section: Introductionmentioning

confidence: 99%

Serelaxin increases the antifibrotic action of rosiglitazone in a model of hepatic fibrosis

Bennett

Simpson

Hamel

2017

WJG

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AIMTo determine the effect of combined serelaxin and rosiglitazone treatment on established hepatic fibrosis.METHODSHepatic fibrosis was induced in mice by carbon tetrachloride administration for 6 wk, or vehicle alone (nonfibrotic mice). For the final 2 wk, mice were treated with rosiglitazone, serelaxin, or both rosiglitazone and serelaxin. Serum liver enzymes and relaxin levels were determined by standard methods. The degree of liver collagen content was determined by histology and immunohistochemistry. Expression of type I collagen was determined by quantitative PCR. Activation of hepatic stellate cells was assessed by alpha-smooth muscle actin (SMA) levels. Liver peroxisome proliferator activated receptor-gamma coactivator 1 alpha (PGC1α) was determined by Western blotting.RESULTSTreatment of mice with CCl4 resulted in hepatic fibrosis as evidenced by increased liver enzyme levels (ALT and AST), and increased liver collagen and SMA. Monotherapy with either serelaxin or rosiglitazone for 2 wk was generally without effect. In contrast, the combination of serelaxin and rosiglitazone resulted in significantly improved ALT levels (P < 0.05). Total liver collagen content as determined by Sirius red staining revealed that only combination treatment was effective in reducing total liver collagen (P < 0.05). These results were supported by immunohistochemistry for type I collagen, in which only combination treatment reduced fibrillar collagen levels (P < 0.05). The level of hepatic stellate cell activation was modestly, but significantly, reduced by serelaxin treatment alone, but combination treatment resulted in significantly lower SMA levels. Finally, while hepatic fibrosis reduced liver PGC1α levels, the combination of serelaxin and rosiglitazone resulted in restoration of PGC1α protein levels.CONCLUSIONThe combination of serelaxin and rosiglitazone treatment for 2 wk was effective in significantly reducing established hepatic fibrosis, providing a potential new treatment strategy.

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Section: Introductionmentioning

confidence: 99%

Serelaxin increases the antifibrotic action of rosiglitazone in a model of hepatic fibrosis

Bennett

Simpson

Hamel

2017

WJG

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“…Risks of all-cause mortality, HCC, cirrhotic decompensation, and hepatic failure did not differ between TZD users and non-users, but TZD users had a significantly higher risk [aHR 1.70 (1.32–2.19)] of major adverse cardiovascular events (composite ischemic heart disease, stroke, and heart failure) than non-users ( 28 ). Our studies suggest that in patients with NAFLD or fibrosis, TZD may be able to slow disease progression ( Table 2 ); however, in the stage of compensated cirrhosis, it may be too late to attenuate cirrhotic deterioration ( Table 1 ) ( 61 ).…”

Section: Management Of Patients With T2d and Chronic Liver Diseasesmentioning

confidence: 89%

Selection and Warning of Evidence-Based Antidiabetic Medications for Patients With Chronic Liver Disease

Yen¹,

Hsu

Wei

et al. 2022

Front. Med.

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The global prevalence of chronic liver disease and diabetes mellitus (DM) has gradually increased potentially due to changes in diet and lifestyle. The choice of antidiabetic medications for patients with coexisting DM and chronic liver disease is complicated. Severe liver injury may decrease the metabolism of antidiabetic medications, resulting in elevated drug concentrations and adverse effects. The choice of antidiabetic medications in patients with chronic liver disease has not been well studied. The long-term outcomes of antidiabetic medications in patients with chronic liver disease have gained attention recently. Herein, we reviewed relevant articles to extend our understanding on the selection and warning of antidiabetic medications for patients with chronic liver disease.

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“…Thiazolidinediones have been shown to be effective antifibrotic agents in CCl 4 treated rats, with positive improvements in histology and profibrotic cytokine profiling. 81 A metaanalysis of 8 randomised clinical trials, including 516 patients diagnosed radiologically or histologically, concluded that thiazolidinedione use for 2 years reversed advanced fibrosis and improved fibrosis stage, even in those without diabetes. 82…”

Section: Thiazolidinedionesmentioning

confidence: 99%

A Review of Liver Fibrosis and Emerging Therapies

Nathwani

Mullish

Kockerling

et al. 2020

EMJ

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With the increasing burden of liver cirrhosis, the most advanced stage of hepatic fibrosis, there is a need to better understand the pathological processes and mechanisms to target specific treatments to reverse or cease fibrosis progression. Antiviral therapy for hepatitis B and C has effectively treated underlying causes of chronic liver disease and has induced fibrosis reversal in some; however, this has not been targeted for the majority of aetiologies for cirrhosis including alcohol or nonalcoholic steatohepatitis. Fibrosis, characterised by the accumulation of extracellular matrix proteins, is caused by chronic injury from toxic, infectious, or metabolic causes. The primary event of fibrogenesis is increased matrix production and scar formation mediated by the hepatic stellate cell, which is the principal cell type involved. Experimental models using rodent and human cell lines of liver injury have assisted in better understanding of fibrogenesis, especially in recognising the role of procoagulant factors. This has led to interventional studies using anticoagulants in animal models with reversal of fibrosis as the primary endpoint. Though these trials have been encouraging, no antifibrotic therapies are currently licenced for human use. This literature review discusses current knowledge in the pathophysiology of hepatic fibrosis, including characteristics of the extracellular matrix, signalling pathways, and hepatic stellate cells. Current types of experimental models used to induce fibrosis, as well as up-to-date anticoagulant therapies and agents targeting the hepatic stellate cell that have been trialled in animal and human studies with antifibrotic properties, are also reviewed.

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Thiazolidinediones and hepatic fibrosis: don't wait too long

Cited by 10 publications

References 27 publications

Serelaxin increases the antifibrotic action of rosiglitazone in a model of hepatic fibrosis

Serelaxin increases the antifibrotic action of rosiglitazone in a model of hepatic fibrosis

Selection and Warning of Evidence-Based Antidiabetic Medications for Patients With Chronic Liver Disease

A Review of Liver Fibrosis and Emerging Therapies

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