Metformin ameliorates bile duct ligation-induced acute hepatic injury via regulation of ER stress
1
조회
0
다운로드
2
인용
0
참고문헌
키워드
초록
Cholestasis is a condition in which the bile duct becomes narrowed or clogged by a variety of factors and bile acid is not released smoothly. Bile acid-induced liver injury is facilitated by necrotic cell death, neutrophil infiltration, and inflammation. Metformin, the first-line treatment for type 2 diabetes, is known to reduce not only blood glucose but also inflammatory responses. In this study, we investigated the effects of metformin on liver injury caused by cholestasis with bile acid-induced hepatocyte injury. Static bile acid-induced liver injury is thought to be related to endoplasmic reticulum (ER) stress, inflammatory response, and chemokine expression. Metformin treatment reduced liver injury caused by bile acid, and it suppressed ER stress, inflammation, chemokine expression, and neutrophil infiltration. Similar results were obtained in mouse primary hepatocytes exposed to bile acid. Hepatocytes treated with tauroursodeoxycholic acid, an ER stress inhibitor, showed inhibition of ER stress, as well as reduced levels of inflammation and cell death. These results suggest that metformin may protect against liver injury by suppressing ER stress and inflammation and reducing chemokine expression.
Abstract
Cholestasis is a condition in which the bile duct becomes narrowed or clogged by a variety of factors and bile acid is not released smoothly. Bile acid-induced liver injury is facilitated by necrotic cell death, neutrophil infiltration, and inflammation. Metformin, the first-line treatment for type 2 diabetes, is known to reduce not only blood glucose but also inflammatory responses. In this study, we investigated the effects of metformin on liver injury caused by cholestasis with bile acid-induced hepatocyte injury. Static bile acid-induced liver injury is thought to be related to endoplasmic reticulum (ER) stress, inflammatory response, and chemokine expression. Metformin treatment reduced liver injury caused by bile acid, and it suppressed ER stress, inflammation, chemokine expression, and neutrophil infiltration. Similar results were obtained in mouse primary hepatocytes exposed to bile acid. Hepatocytes treated with tauroursodeoxycholic acid, an ER stress inhibitor, showed inhibition of ER stress, as well as reduced levels of inflammation and cell death. These results suggest that metformin may protect against liver injury by suppressing ER stress and inflammation and reducing chemokine expression.
참고문헌 (22)
- Bailey CJ, "Metformin", N Engl J Med, 334, pp.574~579 (1996)
- Rena G, "Molecular mechanism of action of metformin: old or new insights?", Diabetologia, 56, pp.1898~1906 (2013)
- Kim J, "Metformin suppresses lipopolysaccharide (LPS)-induced inflammatory response in murine macrophages via activating transcription factor-3 (ATF-3) induction", J Biol Chem, 289, pp.23246~23255 (2014)
- Dai J, "Involvement of catalase in the protective benefits of metformin in mice with oxidative liver injury", Chem Biol Interact, 216, pp.34~42 (2014)
- Wheaton WW, "Metformin inhibits mitochondrial complex I of cancer cells to reduce tumorigenesis", Elife, 3, pp.e02242~ (2014)
- Jung TW, "Metformin prevents endoplasmic reticulum stress-induced apoptosis through AMPK-PI3K-c-Jun NH2 pathway", Biochem Biophys Res Commun, 417, pp.147~152 (2012)
- Trauner M, "Molecular pathogenesis of cholestasis", N Engl J Med, 339, pp.1217~1227 (1998)
- Kaplowitz N, "Drug-induced liver injury", Clin Infect Dis 38 Suppl, 2, pp.S44~S48 (2004)
- Cai SY, "Bile acids initiate cholestatic liver injury by triggering a hepatocyte-specific inflammatory response", JCI Insight, 2, pp.e90780~ (2017)
- Tamaki N, "CHOP deficiency attenuates cholestasis-induced liver fibrosis by reduction of hepatocyte injury", Am J Physiol Gastrointest Liver Physiol, 294, pp.G498~505 (2008)
- Gujral JS, "Neutrophils aggravate acute liver injury during obstructive cholestasis in bile duct-ligated mice", Hepatology, 38, pp.355~363 (2003)
- Schroder M, "ER stress and the unfolded protein response", Mutat Res, 569, pp.29~63 (2005)
- 이다현, "Inactivation of Sirtuin2 protects mice from acetaminophen-induced liver injury: possible involvement of ER stress and S6K1 activation", BMB Reports, 52(3), pp.190~195 (2019), 생화학분자생물학회[DOI]
- 권민영, "Nucleotide-binding oligomerization domain protein 2 attenuates ER stress-induced cell death in vascular smooth muscle cells", BMB Reports, 52(11), pp.665~670 (2019), 생화학분자생물학회[DOI]
- Woudenberg-Vrenken TE, "Metformin protects rat hepatocytes against bile acid-induced apoptosis", PLoS One, 8, pp.e71773~ (2013)
- Tag CG, "Bile duct ligation in mice : induction of inflammatory liver injury and fibrosis by obstructive cholestasis", J Vis Exp, 96, pp.e52438~ (2015)
- Georgiev P, "Characterization of time-related changes after experimental bile duct ligation", Br J Surg, 95, pp.646~656 (2008)
- Afonso MB, "Activation of necroptosis in human and experimental cholestasis", Cell Death Dis, 7, pp.e2390~ (2016)
- Kossor DC, "Biliary epithelial cell proliferation following alpha-naphthylisothiocyanate(ANIT)treatment : relationship to bile duct obstruction", Fundam Appl Toxicol, 26, pp.51~62 (1995)
- Sadeghi H, "Metformin attenuates oxidative stress and liver damage after bile duct ligation in rats", Res Pharm Sci, 14, pp.122~129 (2019)
- Lien F, "Metformin interferes with bile acid homeostasis through AMPK-FXR crosstalk", J Clin Invest, 124, pp.1037~1051 (2014)
- Noguchi H, "Depletion of apoptosis signal-regulating kinase 1 prevents bile duct ligation-induced necroinflammation and subsequent peribiliary fibrosis", Am J Pathol, 184, pp.644~661 (2014)