AMP-activated Protein Kinase α2 Protects against Liver Injury from Metastasized Tumors via Reduced Glucose Deprivation-induced Oxidative Stress

Qiu, Siqi; Xiao, Zhao; Piao, Chunmei; Xian, Ying-Lin; Jia, Lixin; Qi, Young-Fen; Han, Jiahuai; Zhang, Youyi; Du, Jie

doi:10.1074/jbc.m113.543447

Cited by 19 publications

(38 citation statements)

References 51 publications

(61 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Conversely, hypoglycemia in the liver due to fasting, cancer or the effects of T2DM drugs can induce changes in drug metabolism pathways, which can potentially alter drug efficacy and/or toxicity5678. In vitro models of the human liver can supplement animal studies for investigating the progression of disease profiles and drug outcomes given species-specific differences in drug metabolism1524.…”

Section: Discussionmentioning

confidence: 99%

Long-term exposure to abnormal glucose levels alters drug metabolism pathways and insulin sensitivity in primary human hepatocytes

Davidson

Ballinger

Khetani

2016

Sci Rep

View full text Add to dashboard Cite

Hyperglycemia in type 2 diabetes mellitus has been linked to non-alcoholic fatty liver disease, which can progress to inflammation, fibrosis/cirrhosis, and hepatocellular carcinoma. Understanding how chronic hyperglycemia affects primary human hepatocytes (PHHs) can facilitate the development of therapeutics for these diseases. Conversely, elucidating the effects of hypoglycemia on PHHs may provide insights into how the liver adapts to fasting, adverse diabetes drug reactions, and cancer. In contrast to declining PHH monocultures, micropatterned co-cultures (MPCCs) of PHHs and 3T3-J2 murine embryonic fibroblasts maintain insulin-sensitive glucose metabolism for several weeks. Here, we exposed MPCCs to hypo-, normo- and hyperglycemic culture media for ~3 weeks. While albumin and urea secretion were not affected by glucose level, hypoglycemic MPCCs upregulated CYP3A4 enzyme activity as compared to other glycemic states. In contrast, hyperglycemic MPCCs displayed significant hepatic lipid accumulation in the presence of insulin, while also showing decreased sensitivity to insulin-mediated inhibition of glucose output relative to a normoglycemic control. In conclusion, we show for the first time that PHHs exposed to hypo- and hyperglycemia can remain highly functional, but display increased CYP3A4 activity and selective insulin resistance, respectively. In the future, MPCCs under glycemic states can aid in novel drug discovery and mechanistic investigations.

show abstract

Section: Discussionmentioning

confidence: 99%

Long-term exposure to abnormal glucose levels alters drug metabolism pathways and insulin sensitivity in primary human hepatocytes

Davidson

Ballinger

Khetani

2016

Sci Rep

View full text Add to dashboard Cite

show abstract

“…Images were viewed and captured using a Nikon Labophot 2 microscope equipped with a Sony CCD-IRIS/RGB color video camera attached to a computerized imaging system and analyzed by Image Pro Plus 3.0. The expression of Ki-67 was calculated as the proportion of positive area to total tissue area for all measurements of the sections, using the Aperio (Vista, CA) Full Automatic Digital Slide Scanning System (27).…”

Section: Methodsmentioning

confidence: 99%

Complement 5a Enhances Hepatic Metastases of Colon Cancer via Monocyte Chemoattractant Protein-1-mediated Inflammatory Cell Infiltration

Piao

Cai

Qiu

et al. 2015

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

Background: It is known that the complement system contributes to tumor progression, but the exact mechanism is still unclear. Results: Complement 5a enhances tumor metastasis via monocyte chemoattractant protein-1-mediated inflammatory cell infiltration. Conclusion: Complement 5a plays a pro-metastasis role by establishing an inflammatory microenvironment required for tumor metastasis. Significance: Our results provide a therapeutic insight for complement in treatment of malignant tumors.

show abstract

“…Our previous results showed that AMPKα2 deficiency enhanced the glucose deprivation in liver . AMPK is the sensor of energy deprivation .…”

Section: Resultsmentioning

confidence: 95%

“…A liver metastasis model was carried out as described previously . SL4‐luciferase cells, a mouse colon carcinoma cell line with constitutive luciferase expression, were used for this model.…”

Section: Methodsmentioning

confidence: 99%

AMPKα2 knockout enhances tumour inflammation through exacerbated liver injury and energy deprivation‐associated AMPKα1 activation

Qiu

Liu

Piao

et al. 2019

J Cellular Molecular Medi

Self Cite

View full text Add to dashboard Cite

Tissue damage and its associated‐inflammation act as tumour initiators or propagators. AMP ‐activated protein kinase ( AMPK ) is activated by environmental or nutritional stress factors, such as hypoxia, glucose deprivation, and other cell injury factors, to regulate cell energy balance and differentiation. We previously have reported that AMPK α2 deficiency resulted in the energy deprivation in tumour‐bearing liver and the enhanced‐hepatocyte death. In this study, AMPK α2 knockout mice and the liver metastasis model of colon cancer cells were used to address the role of AMPK α isoforms in tumour inflammation. First, we found that the AMPK α2 deficiency exacerbated the liver injury and recruitment of macrophages. Meanwhile, although compensatory expression of AMPK α1 was not significant after AMPK α2 knockout, AMPK α1 phosphorylation was elevated in remnant liver in AMPK α2 knockout mice, which was positively associated with the enhanced energy deprivation in the AMPK α2 deficient mice. Furthermore, the activated AMPK α1 in macrophage contributed to its polarizing to tumour‐associated phenotype. Thus, the enhanced tumour‐associated inflammation and activation of AMPK α1 in the AMPK α2 deficient mice may exacerbate the tumour development by affecting the tumour inflammatory microenvironment. Our study suggests that the two isoforms of AMPK α, AMPK α1 and AMPK α2 play different roles in controlling tumour development.

show abstract

AMP-activated Protein Kinase α2 Protects against Liver Injury from Metastasized Tumors via Reduced Glucose Deprivation-induced Oxidative Stress

Cited by 19 publications

References 51 publications

Long-term exposure to abnormal glucose levels alters drug metabolism pathways and insulin sensitivity in primary human hepatocytes

Long-term exposure to abnormal glucose levels alters drug metabolism pathways and insulin sensitivity in primary human hepatocytes

Complement 5a Enhances Hepatic Metastases of Colon Cancer via Monocyte Chemoattractant Protein-1-mediated Inflammatory Cell Infiltration

AMPKα2 knockout enhances tumour inflammation through exacerbated liver injury and energy deprivation‐associated AMPKα1 activation

Contact Info

Product

Resources

About