High glucose stimulates hepatic stellate cells to proliferate and to produce collagen through free radical production and activation of mitogen‐activated protein kinase

Sugimoto, Rie; Enjoji, Munechika; Kohjima, Motoyuki; Tsuruta, Satoshi; Fukushima, Marie; Iwao, Masataka; Sonta, Toshiyo; Kotoh, Kazuhiro; Inoguchi, Toyoshi; Nakamuta, Makoto

doi:10.1111/j.1478-3231.2005.01130.x

Cited by 107 publications

(86 citation statements)

References 49 publications

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“…Taken together, these data are compatible with p47 phox acting as the organizer subunit for NOX1 in HSCs, although this model presently remains speculative. Proposed functions of NOX-derived ROS in HSCs include the induction of cell proliferation (9,793,838) and the production of collagen (177,838). Consequently, a role for NOX enzymes in hepatic fibrosis, characterized by HSC proliferation and accumulation of extracellular matrix proteins, has been suggested (9,63).…”

Section: Livermentioning

confidence: 99%

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The NOX Family of ROS-Generating NADPH Oxidases: Physiology and Pathophysiology

Bedard¹,

Krause²

2007

Physiological Reviews

5,740

117

5,778

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For a long time, superoxide generation by an NADPH oxidase was considered as an oddity only found in professional phagocytes. Over the last years, six homologs of the cytochrome subunit of the phagocyte NADPH oxidase were found: NOX1, NOX3, NOX4, NOX5, DUOX1, and DUOX2. Together with the phagocyte NADPH oxidase itself (NOX2/gp91phox), the homologs are now referred to as the NOX family of NADPH oxidases. These enzymes share the capacity to transport electrons across the plasma membrane and to generate superoxide and other downstream reactive oxygen species (ROS). Activation mechanisms and tissue distribution of the different members of the family are markedly different. The physiological functions of NOX family enzymes include host defense, posttranlational processing of proteins, cellular signaling, regulation of gene expression, and cell differentiation. NOX enzymes also contribute to a wide range of pathological processes. NOX deficiency may lead to immunosuppresion, lack of otoconogenesis, or hypothyroidism. Increased NOX actvity also contributes to a large number or pathologies, in particular cardiovascular diseases and neurodegeneration. This review summarizes the current state of knowledge of the functions of NOX enzymes in physiology and pathology.

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Section: Livermentioning

confidence: 99%

“…HSCs generate ROS in response to various stimuli (9,63,793,838), particularly TGF-␤ (177). HSCs express p22 phox (46), but which NOX isoform is expressed is less clear.…”

Section: Livermentioning

confidence: 99%

The NOX Family of ROS-Generating NADPH Oxidases: Physiology and Pathophysiology

Bedard¹,

Krause²

2007

Physiological Reviews

5,740

117

5,778

View full text Add to dashboard Cite

show abstract

“…Moreover, a similar close interaction could be observed in patients with other morbidities, such as non-alcoholic fatty liver diseases (NAFLD) (13). Either high glucose or insulin increased the production and expression of collagen genes in activated hepatic stellate cells (HSCs), which play a pivotal role in the liver fibrosis development in vitro (14,15). We previously reported that the IR itself significantly promoted the liver fibrosis development (16).…”

Section: Introductionmentioning

confidence: 84%

Combination of branched-chain amino acid and angiotensin‑converting enzyme inhibitor improves liver fibrosis progression in patients with cirrhosis

et al. 2011

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Abstract. An effective therapeutic strategy for suppressing liver fibrosis should improve the overall prognosis of patients with chronic liver diseases. Although enormous efforts are ongoing to develop anti-fibrotic agents, no drugs have yet been approved as anti-fibrotic agents for humans. Insulin resistance (IR) is reportedly involved in the progression of liver fibrosis. The aim of the present study was to evaluate the effect of combination treatment with a clinically used branched-chain amino acid (BCAA) and an angiotensin-converting enzyme inhibitor (ACE-I) on several fibrotic indices in patients with liver cirrhosis under the condition of IR. BCAA granules (Livact; 12 g/day) and/or ACE-I (perindopril; 4 mg/day) were administered, and several indices were analyzed. A 48-month follow-up revealed that the combination treatment with BCAA and ACE-I markedly improved the progression of serum fibrosis markers, whereas single treatment with either BCAA or ACE-I did not exert these inhibitory effects. The plasma level of transforming growth factor-β was significantly attenuated almost in parallel with the suppression of serum fibrosis markers. Furthermore, the combined treatment with BCAA and ACE-I improved the serum albumin level and IR, which was evaluated using the homeostasis model assessment method for IR. Taken together, since both BCAA and ACE-I are widely used with safety in clinical practice, these results indicate that this combination therapy may represent a potential new future strategy against liver fibrosis development in patients with liver cirrhosis under the condition of IR.

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“…Yang et al (2008) and Sigala et al (2013) reported that noradrenergic cells can induce HSC activation in a dose-dependent manner. Sugimoto et al (2005) reported that high glucose conditions induce HSC activation via the MAPK signaling pathway. External signals can regulate HSC activation via the p38-MAPK signaling pathway, thereby regulating hepatic fibrosis.…”

Section: Discussionmentioning

confidence: 99%

High levels of glucose promote the activation of hepatic stellate cells via the p38-mitogen-activated protein kinase signal pathway

Wu¹,

Liu²,

Ma³

et al. 2016

Genet. Mol. Res.

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ABSTRACT.The relationship between the p38-mitogen-activated protein kinase (p38-MAPK) signal pathway and high glucose-induced hepatic stellate cell (HSC) activation was investigated in this study. Sixty human HSC samples were randomly selected and used in the control (cultured normally), high-glucose (cultured in the presence of high glucose), and blocking (cultured under high-glucose conditions in the presence of the p38-MAPK inhibitor, SB203580) groups. The cells were incubated for 120 h and subsequently analyzed for morphological changes by inverted microscopy and for a-smooth muscle actin (a-SMA) expression (to determine the degree of HSC activation) by the method of streptavidin-biotin complex and western blot. Phospho-p38-MAPK protein expression was analyzed by western blotting. a-SMA and phospho-p38-MAPK expression was significantly upregulated in HSCs cultured under high-glucose conditions, compared to the HSCs cultured normally (P < 0.01). On the other hand, phospho-p38-MAPK and a-SMA protein levels were significantly lower in the blocking group compared to the high-glucose group (P < 0.01). Based on these results, we concluded that high-glucose levels induce HSC activation mediated by phospho-p38-MAPK. Therefore, blocking the p38-MAPK signal pathway could inhibit this effect.

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High glucose stimulates hepatic stellate cells to proliferate and to produce collagen through free radical production and activation of mitogen‐activated protein kinase

Abstract: Our findings indicate that high glucose concentrations may stimulate ROS production through PKC-dependent activation of NADPH oxidase, and induce MAP kinase phosphorylation subsequent to proliferation and type I collagen production by HSCs.

Cited by 107 publications

References 49 publications

The NOX Family of ROS-Generating NADPH Oxidases: Physiology and Pathophysiology

The NOX Family of ROS-Generating NADPH Oxidases: Physiology and Pathophysiology

Combination of branched-chain amino acid and angiotensin‑converting enzyme inhibitor improves liver fibrosis progression in patients with cirrhosis

High levels of glucose promote the activation of hepatic stellate cells via the p38-mitogen-activated protein kinase signal pathway

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