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Astaxanthin attenuates the increase in mitochondrial respiration during the activation of hepatic stellate cells.

ABSTRACT: Upon liver injury, quiescent hepatic stellate cells (qHSCs) transdifferentiate to myofibroblast-like activated HSCs (aHSCs), which are primarily responsible for the accumulation of extracellular matrix proteins during the development of liver fibrosis. Therefore, aHSCs may exhibit different energy metabolism from that of qHSCs to meet their high energy demand. We previously demonstrated that astaxanthin (ASTX), a xanthophyll carotenoid, prevents the activation of HSCs. The objective of this study was to determine if ASTX can exert its antifibrogenic effect by attenuating any changes in energy metabolism during HSC activation. To characterize the energy metabolism of qHSCs and aHSCs, mouse primary HSCs were cultured on uncoated plastic dishes for 7 days for spontaneous activation in the presence or absence of 25 ?M ASTX. qHSCs (1 day after isolation) and aHSCs treated with or without ASTX for 7 days were used to determine parameters related to mitochondrial respiration using a Seahorse XFe24 Extracellular Flux analyzer. aHSCs had significantly higher basal respiration, maximal respiration, ATP production, spare respiratory capacity and proton leak than those of qHSCs. However, ASTX prevented most of the changes occurring during HSC activation and improved mitochondrial cristae structure with decreased cristae junction width, lumen width and the area in primary mouse aHSCs. Furthermore, qHSCs isolated from ASTX-fed mice had lower mitochondrial respiration and glycolysis than control qHSCs. Our findings suggest that ASTX may exert its antifibrogenic effect by attenuating the changes in energy metabolism during HSC activation.

SUBMITTER: Bae M

PROVIDER: S-EPMC6707861 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Astaxanthin attenuates the increase in mitochondrial respiration during the activation of hepatic stellate cells.

Bae Minkyung M Lee Yoojin Y Park Young-Ki YK Shin Dong-Guk DG Joshi Pujan P Hong Seung-Hyun SH Alder Nathan N Koo Sung I SI Lee Ji-Young JY

The Journal of nutritional biochemistry 20190620

Upon liver injury, quiescent hepatic stellate cells (qHSCs) transdifferentiate to myofibroblast-like activated HSCs (aHSCs), which are primarily responsible for the accumulation of extracellular matrix proteins during the development of liver fibrosis. Therefore, aHSCs may exhibit different energy metabolism from that of qHSCs to meet their high energy demand. We previously demonstrated that astaxanthin (ASTX), a xanthophyll carotenoid, prevents the activation of HSCs. The objective of this stud ...[more]

PMID: 31302374

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Project description:The loss of mitochondrial function impairs intracellular energy production and potentially results in chronic liver disease. Increasing evidence suggests that mitochondrial dysfunction in hepatocytes contributes to the activation of hepatic stellate cells (HSCs), thereby resulting in hepatic fibrogenesis. High-temperature requirement protein A2 (HtrA2/Omi), a mitochondrial serine protease with various functions, is responsible for quality control in mitochondrial homeostasis. However, little information is available regarding its role in mitochondrial damage during the development of liver fibrosis. This study examined whether HtrA2/Omi regulates mitochondrial homeostasis in hepatocyte during the development of hepatic fibrogenesis. In this study, we demonstrated that HtrA2/Omi expression considerably decreased in liver tissues from the CCl4-induced liver fibrotic mice model and from patients with liver cirrhosis. Knockdown of HtrA2/Omi in hepatocytes induced the accumulation of damaged mitochondria and provoked mitochondrial reactive oxygen species (mtROS) stress. We further show that the damaged mtDNA isolated from HtrA2/Omi-deficient hepatocytes as a form of damage-associated molecular patterns can induce HSCs activation. Moreover, we found that motor neuron degeneration 2-mutant mice harboring the missense mutation Ser276Cys in the protease domain of HtrA2/Omi displayed altered mitochondrial morphology and function, which increased oxidative stress and promoted liver fibrosis. Conversely, the overexpression of HtrA2/Omi via hydrodynamics-based gene transfer led to the antifibrotic effects in CCl4-induced liver fibrosis mice model through decreasing collagen accumulation and enhancing anti-oxidative activity by modulating mitochondrial homeostasis in the liver. These results suggest that suppressing HtrA2/Omi expression promotes hepatic fibrogenesis via modulating mtROS generation, and these novel mechanistic insights involving the regulation of mitochondrial homeostasis by HtrA2/Omi may be of importance for developing new therapeutic strategies for hepatic fibrosis.

Dataset Information

Astaxanthin attenuates the increase in mitochondrial respiration during the activation of hepatic stellate cells.

Publications

Astaxanthin attenuates the increase in mitochondrial respiration during the activation of hepatic stellate cells.

Similar Datasets

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