Cover Story Current Issue
Weaning involves a dietary switch in mammals, progressively decreasing the reliance on the consumption of a fat-rich milk diet in favour of a carbohydrate-rich diet. Metabolic adaptation to this shift in macronutrient consumption is characterized by reduced hepatic gluconeogenesis, increased liver glycogen content, and changes in lipid metabolism. Such metabolic changes are supported by various nutritional, hormonal, and neuronal factors. Dietary changes during weaning are shown to drive β-cell proliferation and maturation, which is important for the optimal endocrine function of the pancreas. A switch from the nutrient sensor target of rapamycin (mTORC1) to the energy sensor 5′-adenosine monophosphate-activated protein kinase (AMPK) was found critical for functional maturation of β-cells. Furthermore, changes in the macronutrient composition during the weaning process drive alterations in the gut microbiome, which is essential for the development of immune tolerance. The major calcium absorption pathway also changes during weaning, from the paracellular pathway during the suckling stage to the vitamin D dependent transcellular pathway post-weaning. However, the factors that regulate these post-weaning metabolic adaptations are not fully understood.
Current Issue
Conditional deletion of CEACAM1 in hepatic stellate cells causes their activation
Conditional deletion of CEACAM1 in hepatic stellate cells causes their activation
Objectives
Hepatic CEACAM1 expression declines with advanced hepatic fibrosis stage in patients with metabolic dysfunction-associated steatohepatitis (MASH). Global and hepatocyte-specific deletions of Ceacam1 impair insulin clearance to cause hepatic insulin resistance and steatosis. They also cause hepatic inflammation and fibrosis, a condition characterized by excessive collagen production from activated hepatic stellate cells (HSCs). Given the positive effect of PPARγ on CEACAM1 transcription and on HSCs quiescence, the current studies investigated whether CEACAM1 loss from HSCs causes their activation.
Methods
We examined whether lentiviral shRNA-mediated CEACAM1 donwregulation (KD-LX2) activates cultured human LX2 stellate cells. We also generated LratCre + Cc1fl/fl mutants with conditional Ceacam1 deletion in HSCs and characterized their MASH phenotype. Media transfer experiments were employed to examine whether media from mutant human and murine HSCs activate their wild-type counterparts.
Results
LratCre + Cc1fl/fl mutants displayed hepatic inflammation and fibrosis but without insulin resistance or hepatic steatosis. Their HSCs, like KD-LX2 cells, underwent myofibroblastic transformation and their media activated wild-type HSCs. This was inhibited by nicotinic acid treatment which blunted the release of IL-6 and fatty acids, both of which activate the epidermal growth factor receptor (EGFR) tyrosine kinase. Gefitinib inhibition of EGFR and its downstream NF-κB/IL-6/STAT3 inflammatory and MAPK-proliferation pathways also blunted HSCs activation in the absence of CEACAM1.
Conclusions
Loss of CEACAM1 in HSCs provoked their myofibroblastic transformation in the absence of insulin resistance and hepatic steatosis. This response is mediated by autocrine HSCs activation of the EGFR pathway that amplifies inflammation and proliferation.
Articles in Press
Conditional deletion of CEACAM1 in hepatic stellate cells causes their activation
Conditional deletion of CEACAM1 in hepatic stellate cells causes their activation
Objectives
Hepatic CEACAM1 expression declines with advanced hepatic fibrosis stage in patients with metabolic dysfunction-associated steatohepatitis (MASH). Global and hepatocyte-specific deletions of Ceacam1 impair insulin clearance to cause hepatic insulin resistance and steatosis. They also cause hepatic inflammation and fibrosis, a condition characterized by excessive collagen production from activated hepatic stellate cells (HSCs). Given the positive effect of PPARγ on CEACAM1 transcription and on HSCs quiescence, the current studies investigated whether CEACAM1 loss from HSCs causes their activation.
Methods
We examined whether lentiviral shRNA-mediated CEACAM1 donwregulation (KD-LX2) activates cultured human LX2 stellate cells. We also generated LratCre + Cc1fl/fl mutants with conditional Ceacam1 deletion in HSCs and characterized their MASH phenotype. Media transfer experiments were employed to examine whether media from mutant human and murine HSCs activate their wild-type counterparts.
Results
LratCre + Cc1fl/fl mutants displayed hepatic inflammation and fibrosis but without insulin resistance or hepatic steatosis. Their HSCs, like KD-LX2 cells, underwent myofibroblastic transformation and their media activated wild-type HSCs. This was inhibited by nicotinic acid treatment which blunted the release of IL-6 and fatty acids, both of which activate the epidermal growth factor receptor (EGFR) tyrosine kinase. Gefitinib inhibition of EGFR and its downstream NF-κB/IL-6/STAT3 inflammatory and MAPK-proliferation pathways also blunted HSCs activation in the absence of CEACAM1.
Conclusions
Loss of CEACAM1 in HSCs provoked their myofibroblastic transformation in the absence of insulin resistance and hepatic steatosis. This response is mediated by autocrine HSCs activation of the EGFR pathway that amplifies inflammation and proliferation.
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12th Helmholtz
Diabetes Conference
22-24. Sep, Munich
2022 impact factor: 6.6
You are what you eat
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