Hepatic stress associated with pathologies characterized by disturbed glucose production
Authors:Monika Gjorgjieva1-3,#, Gilles Mithieux1-3 and Fabienne Rajas1-3
1 Institut National de la Santé et de la Recherche Médicale, U1213, Lyon, F-69008, France.
2 Université de Lyon, Lyon, F-69008 France.
3 Université Lyon I, Villeurbanne, F-69622 France.
# Current address: Université de Genève, Geneva, 1211 Switzerland.
Keywords:
glucose-6 phosphate, diabetes, glycogen storage disease type I, glucotoxicity, lipotoxicity, NAFLD, hepatic tumors.
Abbreviations:
AGE –advanced glycation end-product,
ChREBP – carbohydrate response element binding protein,
ECM – extracellular matrix,
EGP – endogenous glucose production,
G6P- glucose-6-phosphate,
G6Pase – glucose-6-phosphatase,
GNG – gluconeogenesis,
GSDI – glycogen storage disease type I,
HCA – hepatocellular adenoma,
HCC – hepatocellular carcinoma,
iNOS – inducible nitric oxide synthase,
NAFLD – non-alcoholic fatty liver disease,
NEFA – non-esterified fatty acid,
PPP – pentose phosphate pathway,
ROS – reactive oxygen species,
SREBP-1c – sterole regulatory element binding protein-1c,
TG – triglyceride,
TNFα – tumor necrosis factor alpha,
VLDL – very low density lipoprotein.
Corresponding Author(s):
Conflict of interest statement:
The authors declare no conflict of interest.
Please cite this article as:
Monika Gjorgjieva, Gilles Mithieux and Fabienne Rajas (2019). Hepatic stress associated with pathologies char-acterized by disturbed glucose production. Cell Stress 3(3): 86-99. doi: 10.15698/cst2019.03.179
© 2019 Gjorgjieva et al. This is an open-access article released under the terms of the Creative Commons Attribution (CC BY) license, which allows the unrestricted use, distribution, and reproduc-tion in any medium, provided the original author and source are acknowledged.
Abstract:
The liver is an organ with many facets, including a role in energy production and metabolic balance, detoxification and extraordinary capacity of regeneration. Hepatic glucose production plays a crucial role in the maintenance of normal glucose levels in the organism i.e. between 0.7 to 1.1 g/l. The loss of this function leads to a rare genetic metabolic disease named glycogen storage disease type I (GSDI), characterized by severe hypoglycemia during short fasts. On the contrary, type 2 diabetes is characterized by chronic hyperglycemia, partly due to an overproduction of glucose by the liver. Indeed, diabetes is characterized by increased uptake/production of glucose by hepatocytes, leading to the activation of de novo lipogenesis and the development of a non-alcoholic fatty liver disease. In GSDI, the accumulation of glucose-6 phosphate, which cannot be hydrolyzed into glucose, leads to an increase of glycogen stores and the development of hepatic steatosis. Thus, in these pathologies, hepatocytes are subjected to cellular stress mainly induced by glucotoxicity and lipotoxicity. In this review, we have compared hepatic cellular stress induced in type 2 diabetes and GSDI, especially oxidative stress, autophagy deregulation, and ER-stress. In addition, both GSDI and diabetic patients are prone to the development of hepatocellular adenomas (HCA) that occur on a fatty liver in the absence of cirrhosis. These HCA can further acquire malignant traits and transform into hepatocellular carcinoma. This process of tumorigenesis highlights the importance of an optimal metabolic control in both GSDI and diabetic patients in order to prevent, or at least to restrain, tumorigenic activity during disturbed glucose metabolism pathologies.