NADPH oxidase signal transduces angiotensin II in hepatic stellate cells and is critical in hepatic fibrosis

Bataller, Ramón; Schwabe, Robert F.; Choi, You-kyung; Yang, Liu; Paik, Yong Han; Lindquist, Jeffrey N.; Qian, Ting; Schoonhoven, Robert; Hagedorn, Curt H.; Lemasters, John J.; Brenner, David A.

doi:10.1172/jci18212

Cited by 506 publications

(403 citation statements)

References 54 publications

(36 reference statements)

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“…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). In fact, analysis of cellular phenotype revealed a slight, but significant, activation of HSC, supported by increments in different activation markers including α‐SMA or collagen I.…”

Section: Discussionsupporting

confidence: 82%

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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Section: Discussionsupporting

confidence: 82%

Effects of aging on liver microcirculatory function and sinusoidal phenotype

et al. 2018

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“…Key components of the renin-angiotensin system are locally expressed in chronically injured livers, and activated HSCs generate angiotensin II de novo [108]. In HSCs, angiotensin II induces proliferation and migration, the secretion of proinflammatory cytokines, and collagen synthesis [109,110]. The hormone also affects HSCs by increasing the intracellular concentration of Ca 2 ?…”

Section: Renin-angiotensin Systemmentioning

confidence: 99%

Inflammation and fibrogenesis in steatohepatitis

2012

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Nonalcoholic fatty liver disease consists of a range of disorders characterized by excess accumulation of triglyceride within the liver. Whereas simple steatosis is clinically benign, nonalcoholic steatohepatitis (NASH) often progresses to cirrhosis. Inflammation and fibrogenesis are closely inter-related and are major targets of NASH research. Experimental data have shown that inflammation in NASH is caused by insulin resistance, systemic lipotoxicity due to overnutrition, lipid metabolites, the production of proinflammatory cytokines and adipokines by visceral adipose tissue, gut-derived bacteria, and oxidative stress. In NASH-associated fibrosis, the principal cell type responsible for extracellular matrix production is recognized as the hepatic stellate cell. Although the fibrotic mechanisms underlying NASH are largely similar to those observed in other chronic liver diseases, the altered patterns of circulating adipokines, the generation of oxidative stress, and the hormonal profile associated with the metabolic syndrome might play unique roles in the fibrogenesis associated with the disease. Information on the basic pathogenesis of NASH with a focus on the generation of inflammation and fibrosis will be discussed.

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“…52,91 In fact, it has also been demonstrated that angiotensin II and norepinephrine released from adipose tissues directly activate hepatic stellate cells. [92][93][94] The livers of NASH patients frequently "burn out," in the process of developing liver cirrhosis, and such patients are considered to have cryptogenic cirrhosis. These patients account for around 10% of all patients with cirrhosis in Okinawa, Japan.…”

Section: Vldl Release From Hepatocytesmentioning

confidence: 99%

Clinical features of nonalcoholic steatohepatitis in Japan: evidence from the literature

Ono

Saibara

2006

J Gastroenterol

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Metabolic syndrome, that is, obesity, hypertension, hyperlipidemia, and insulin resistance with hyperinsulinemia, is a new disease entity prevailing worldwide, and nonalcoholic steatohepatitis (NASH) is believed to be a hepatic expression of this syndrome. NASH is characterized by zone 3-dominant hepatic steatosis with ballooned hepatocytes and Mallory bodies, zone 3 pericellular and perivenular fibrosis with or without bridging fibrosis, and lobular inflammatory cell infiltration. Indeed, 90% of NASH has been revealed to be complicated by visceral obesity, and two-thirds of NASH patients fulfill the criteria of metabolic syndrome. Therefore, a variety of lifestyle-related diseases such as obesity, hypertension, hyperlipidemia, and diabetes mellitus may share the same background. NASH is most prevalent and well characterized in Caucasians; however, little is known about its occurrence in Asia-Oceania, because obesity has not been frequent in countries in these areas. Obesity is expected to become a serious social problem in Asia-Oceania in the next two decades, so we need to prevent a corresponding increase of NASH. For that purpose, we need to know much about not only NASH but also ourselves. To elucidate the status of NASH in Japan, recent progress in the study of NASH in Japan is reviewed in this article.

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NADPH oxidase signal transduces angiotensin II in hepatic stellate cells and is critical in hepatic fibrosis

Cited by 506 publications

References 54 publications

Effects of aging on liver microcirculatory function and sinusoidal phenotype

Effects of aging on liver microcirculatory function and sinusoidal phenotype

Inflammation and fibrogenesis in steatohepatitis

Clinical features of nonalcoholic steatohepatitis in Japan: evidence from the literature

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