The Effects of Old Age on Hepatic Stellate Cells

Warren, Alessandra; Cogger, Victoria C.; Fraser, Robin; DeLeve, Laurie D.; McCuskey, Robert S.; Couteur, David G. Le

doi:10.1155/2011/439835

Cited by 38 publications

(41 citation statements)

References 17 publications

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“…Taken together, the extent of HSC clearance achieved during interferon therapy could explain the long‐term benefit, in the basis of controlled HIV infection . In this way, the influence of age in fibrosis regression observed in several studies , including this, supports the influence of HSC, as older age is associated with hyperplasia of HSC in animal models .…”

Section: Discussionsupporting

confidence: 70%

Regression of liver fibrosis is progressive after sustained virological response to HCV therapy in patients with hepatitis C and HIV coinfection

Casado¹,

Quereda²,

Moreno³

et al. 2013

Journal of Viral Hepatitis

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There are few data about the long-term histological outcome of HIV-/HCV-coinfected patients after therapy with interferon and ribavirin. We performed an observational study of 216 patients who received therapy against HCV and who had at least three successive transient elastographies (TE) during the follow-up. The primary endpoint was confirmed fibrosis regression, defined as a reduction of at least 1 point in Metavir fibrosis score, confirmed and without worsening in successive TE. At baseline, 23% had fibrosis stage 4 or cirrhosis. Overall, 82 (38%) achieved sustained virological response (SVR), without differences in baseline fibrosis or time of follow-up. Confirmed fibrosis regression was observed in 55% of patients, higher for SVR (71% vs 44%; P < 0.01), and the likelihood of achieving fibrosis regression at 3, 5 and 7 years was 0.17, 0.51 and 0.67, respectively, for SVR patients, in comparison with 0.02, 0.23 and 0.41 for no SVR patients (P < 0.01, log-rank test at any time point). Progressive regression, defined as continuous improvement in successive TE, was observed in 62% of patients with advanced liver fibrosis or cirrhosis who achieved SVR. In a Cox regression model, only SVR (HR, 4.01; 95% CI, 2.33-7.57; P < 0.01) and a younger age (HR, 1.14; 95% CI, 1.05-1.25; P < 0.01; per year) were associated with fibrosis regression. This study confirms that the rate of liver fibrosis regression increases during the follow-up after SVR to interferon therapy in HIV-/HCV-coinfected patients.

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Section: Discussionsupporting

confidence: 70%

Regression of liver fibrosis is progressive after sustained virological response to HCV therapy in patients with hepatitis C and HIV coinfection

Casado¹,

Quereda²,

Moreno³

et al. 2013

Journal of Viral Hepatitis

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“…Next, we examined the effects of SIRT1 in hepatic HSCs, one of the main cell types responsible for liver fibrogenesis [31]. As illustrated in Fig.…”

Section: Resultsmentioning

confidence: 99%

Aging aggravates alcoholic liver injury and fibrosis in mice by downregulating sirtuin 1 expression

Ramírez

Yin

et al. 2017

Journal of Hepatology

135

112

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Background and Aims Aging is known to exacerbate the progression of alcoholic liver disease (ALD), but the underlying mechanisms remain obscure. Methods C57BL/6 mice were subjected to short-term (10-days) ethanol-plus-one binge or long- term (8-weeks) ethanol-plus-multiple binges of ethanol. Liver injury and fibrosis were determined. Hepatic stellate cells (HSCs) were isolated and used in in vitro studies. Results Compared to young (8–12 weeks) mice, middle-aged (12–14 months) and old (>16 months) mice were more susceptible to liver injury, inflammation, and oxidative stress induced by short-term-plus-one binge or long-term-plus-multiple binges of ethanol feeding. Long-term-plus- multiple binges of ethanol feeding induced greater liver fibrosis in middle-aged mice than that in young mice. Hepatic expression of Sirtuin 1 (SIRT1) protein was downregulated in the middle-aged mice compared to young mice. Restoration of SIRT1 expression via the administration of adenovirus-SIRT1 vector ameliorated short-term-plus-binge ethanol-induced liver injury and fibrosis in middle-aged mice. HSCs isolated from middle-aged mice expressed lower levels of SIRT1 protein and were more susceptible to spontaneous activation in in vitro culture than those from young mice. Overexpression of SIRT1 reduced activation of HSCs from middle-aged mice in vitro with downregulation of PDGFR-α and c-Myc, while deletion of SIRT1 activated HSCs isolated from young mice in vitro. Finally, HSC-specific SIRT1 knockout mice were more susceptible to short-term-plus-binge ethanol-induced liver fibrosis with upregulation of PDGFR-α expression. Conclusions Aging exacerbates ALD in mice through the downregulation of SIRT1 in hepatocytes and HSCs. Activation of SIRT1 may serve as a novel target for the treatment of ALD.

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“…A previous report described increased number of fatty HSC in the aged liver (Warren et al, 2011); however, no comprehensive analysis of stellate cells phenotype in aging has been conducted. Herein, we confirm lipid accumulation within aged HSC and additionally describe increments in other mediators of HSC activation including intracellular oxidative stress and p16 (Bataller et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

Effects of aging on liver microcirculatory function and sinusoidal phenotype

et al. 2018

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The socioeconomic and medical improvements of the last decades have led to a relevant increase in the median age of worldwide population. Although numerous studies described the impact of aging in different organs and the systemic vasculature, relatively little is known about liver function and hepatic microcirculatory status in the elderly. In this study, we aimed at characterizing the phenotype of the aged liver in a rat model of healthy aging, particularly focusing on the microcirculatory function and the molecular status of each hepatic cell type in the sinusoid. Moreover, major findings of the study were validated in young and aged human livers. Our results demonstrate that healthy aging is associated with hepatic and sinusoidal dysfunction, with elevated hepatic vascular resistance and increased portal pressure. Underlying mechanisms of such hemodynamic disturbances included typical molecular changes in the cells of the hepatic sinusoid and deterioration in hepatocyte function. In a specific manner, liver sinusoidal endothelial cells presented a dysfunctional phenotype with diminished vasodilators synthesis, hepatic macrophages exhibited a proinflammatory state, while hepatic stellate cells spontaneously displayed an activated profile. In an important way, major changes in sinusoidal markers were confirmed in livers from aged humans. In conclusion, our study demonstrates for the first time that aging is accompanied by significant liver sinusoidal deregulation suggesting enhanced sinusoidal vulnerability to chronic or acute injuries.

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The Effects of Old Age on Hepatic Stellate Cells

Cited by 38 publications

References 17 publications

Regression of liver fibrosis is progressive after sustained virological response to HCV therapy in patients with hepatitis C and HIV coinfection

Regression of liver fibrosis is progressive after sustained virological response to HCV therapy in patients with hepatitis C and HIV coinfection

Aging aggravates alcoholic liver injury and fibrosis in mice by downregulating sirtuin 1 expression

Effects of aging on liver microcirculatory function and sinusoidal phenotype

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