Activation of the Hypoxia Inducible Factor 1α Subunit Pathway in Steatotic Liver Contributes to Formation of Cholesterol Gallstones

Asai, Yoichiro; Yamada, Tetsuya; Tsukita, Sohei; Takahashi, Kei; Maekawa, Masamitsu; Honma, Midori; Ikeda, Masanori; Murakami, Keigo; Munakata, Yasuhiko; Shirai, Yuta; Kodama, Shohei; Sugisawa, Takashi; Chiba, Yu; Kondo, Yasuteru; Kaneko, Keizo; Uno, Kenji; Sawada, Shojiro; Imai, Junta; Nakamura, Yasuhiro; Yamaguchi, Hiroaki; Tanaka, Kozo; Sasano, Hironobu; Mano, Nariyasu; Ueno, Yoshiyuki; Shimosegawa, Tooru; Katagiri, Hideki

doi:10.1053/j.gastro.2017.01.001

Cited by 52 publications

(41 citation statements)

References 75 publications

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“…Premetastatic liver cells of melanoma B16‐bearing mice exhibited the opposite pattern, as they displayed more intensive VEGFA immunostaining of endothelial cells localized in the large median hepatic lobe. The levels of VEGFA are known to be increased under hypoxic conditions, which explains the more prominent VEGFA expression in the periphery of the normal liver. In the premetastatic liver, the VEGFA expression was increased in the central parts of the organ, which was consistent with reported data on the upregulation of VEGFA in synchronous liver metastasis‐adjacent tissue compared with metastatic tissue per se in colorectal carcinoma .…”

Section: Discussionmentioning

confidence: 99%

miR‐155 overexpression is followed by downregulation of its target gene, NFE2L2, and altered pattern of VEGFA expression in the liver of melanoma B16‐bearing mice at the premetastatic stage

Aksenenko

Palkina

Сергеева

et al. 2019

Int J Experimental Path

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Summary MicroRNAs are involved in the control of tumour progression and in metastatic cascade dynamics. However, the role of microRNAs in distant organ reorganization at the premetastatic stage is less clear, although the process of premetastatic niche formation is a crucial event according to modern concepts of tumour dissemination. The role of the present study was to investigate the expression levels of miR‐155, miR‐21, miR‐205 and miR‐let7b, as well as that of their target genes, in target organs of melanoma metastasis at the premetastatic stage. The expression levels of both the pro‐oncogenic miR‐155 and the tumour suppressive miR‐205 were found to be altered in the premetastatic liver of melanoma B16‐bearing mice. Bioinformatics analysis identified the target genes of miR‐155 to be nuclear factor, erythroid 2 like 2 (NFE2L2), secretogranin II, miR‐205, semaphorin 5A and vascular endothelial growth factor A (VEGFA). Among those, the redox status regulatory factor NFE2L2 was downregulated, which corresponded to increased levels of miR‐155. Due to the ability of pro‐oxidative events to initiate angiogenesis, VEGFA levels were evaluated in the premetastatic liver by immunohistochemistry, which revealed increased VEGFA expression in the central parts of the organ and diminished expression in the periphery. Taken together, these findings may support the concept of functional organ reorganization due to melanoma progression.

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Section: Discussionmentioning

confidence: 99%

miR‐155 overexpression is followed by downregulation of its target gene, NFE2L2, and altered pattern of VEGFA expression in the liver of melanoma B16‐bearing mice at the premetastatic stage

Aksenenko

Palkina

Сергеева

et al. 2019

Int J Experimental Path

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“…Relative changes in gene expressions were determined using the 2 -ΔΔCt method. ΔCt refers to the cycle number at which the transcripts were detectable (Ct) normalized to the cycle number of CDKN1B [ 27 ]…”

Section: Methodsmentioning

confidence: 99%

Selective insulin resistance with differential expressions of IRS-1 and IRS-2 in human NAFLD livers

et al. 2018

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Background/objective:Insulin signals, via the regulation of key enzyme expression, both suppress gluconeogenesis and enhance lipid synthesis in the liver. Animal studies have revealed insulin signaling favoring gluconeogenesis suppression to be selectively impaired in steatotic livers. However, whether, and if so how, such selective insulin resistance occurs in human steatotic livers remains unknown. Our aim was to investigate selective insulin resistance in human livers with non-alcoholic fatty liver disease (NAFLD).Subjects/methods:We examined mRNA expressions of key molecules for insulin signaling, gluconeogenesis and lipogenesis in human liver biopsy samples obtained from 51 non-diabetic subjects: 9 healthy controls and 42 NAFLD patients, and analyzed associations of these molecules with each other and with detailed pathological and clinical biochemistry data.Results:In NAFLD patients, insulin receptor substrate (IRS)-2 expression was decreased, while those of key enzymes for gluconeogenesis were increased. These alterations of IRS-2 and gluconeogenesis enzymes were induced both in simple steatosis (SS) and non-alcoholic steatohepatitis (NASH), while these expression levels did not differ between SS and NASH. Furthermore, alterations in the expressions of IRS-2 and gluconeogenesis enzymes showed strong negative correlations and were concurrently induced in the early histological stage of NAFLD. In contrast, fatty acid synthase (FAS) expression was not decreased in NAFLD, despite IRS-2 downregulation, but correlated strongly with IRS-1 expression. Furthermore, no histological scores were associated with these molecules. Thus, IRS-1 signaling, which is not impaired in NAFLD, appears to modulate FAS expression.Conclusion:These analyses revealed that selective insulin resistance is present in human NAFLD livers and occurs in its early phases. The effect of insulin, during the IRS step, on gene expressions for lipogenesis and gluconeogenesis are apparently distinct and preferential downregulation of IRS-2 may contribute to selective resistance to the suppressive effects of insulin on gluconeogenesis.

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“…Asai et al . [60 ▪▪ ] found that expression of aquaporin-8 (AQP8), a water channel that is responsible for hepatic water secretion into the bile canaliculi [61–63], is markedly increased in the inducible hepatocyte-selective HIF1A knockout mice fed the lithogenic diet for 2 weeks. These changes dramatically increase bile flow by 35%, dilute biliary lipid concentrations by 36% in both gallbladder and hepatic bile, and alleviate gallbladder inflammation.…”

Section: The Latest Advances In the Pathophysiology Of Gallstones Fromentioning

confidence: 99%

Mouse models of gallstone disease

Wang

Portincasa

Liu

et al. 2018

Current Opinion in Gastroenterology

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Purpose of review The establishment of mouse models of gallstones, and the contribution of mouse models to genetic studies of gallstone disease, as well as the latest advances in the pathophysiology of gallstones from mouse experiments are summarized. Recent findings The combined uses of genomic strategies and phenotypic studies in mice have successfully led to the identification of many Lith genes, which pave the way for the discovery of human LITH genes. The physical–chemical, genetic, and molecular biological studies of gallstone disease in mice with knockout or transgene of specific target genes have provided many novel insights into the complex pathophysiological mechanisms of this very common hepatobiliary disease worldwide, showing that interactions of five primary defects play a critical role in the pathogenesis of cholesterol gallstones. Based on mouse studies, a new concept has been proposed that hepatic hypersecretion of biliary cholesterol is induced by multiple Lith genes, with insulin resistance as part of the metabolic syndrome interacting with cholelithogenic environmental factors to cause the phenotype. Summary The mouse model of gallstones is crucial for elucidating the physical–chemical and genetic mechanisms of cholesterol crystallization and gallstone formation, which greatly increase our understanding of the pathogenesis of this disease in humans.

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Activation of the Hypoxia Inducible Factor 1α Subunit Pathway in Steatotic Liver Contributes to Formation of Cholesterol Gallstones

Cited by 52 publications

References 75 publications

miR‐155 overexpression is followed by downregulation of its target gene, NFE2L2, and altered pattern of VEGFA expression in the liver of melanoma B16‐bearing mice at the premetastatic stage

miR‐155 overexpression is followed by downregulation of its target gene, NFE2L2, and altered pattern of VEGFA expression in the liver of melanoma B16‐bearing mice at the premetastatic stage

Selective insulin resistance with differential expressions of IRS-1 and IRS-2 in human NAFLD livers

Mouse models of gallstone disease

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