STEATOSIS CAUSES HEPATIC IRON RESISTANCE IN TYPE 2 DIABETES.
Type 2 diabetes mellitus (T2DM) is a metabolic disorder hallmarked by hyperglycaemia due to insulin resistance, increased body mass index and hepatic steatosis.
We have previously demonstrated that T2DM patients show inappropriately low hepcidin levels despite increased systemic iron. Analysis of the db/db mouse model of T2DM further showed an “iron resistance” phenotype, whereby the steatotic liver is iron deficient in the presence of increased plasma iron levels.
We now aim to identify the mechanism(s) how T2DM causes hepatic iron resistance. We excluded hyperglycaemia and reduced insulin-related signalling, since iron-parameters remained unaltered in non-obese insulin-deficient Ins2(Akita) mice. We next generated the western diet-induced model of NAFLD. These mice show normoglycemia and unaltered expression of key genes involved in glycolysis and gluconeogenesis compared to wild-type mice. In this model, the liver is steatotic and iron deficient while plasma iron levels are elevated, mirroring T2DM. Hepcidin mRNA expression is strongly decreased even though mRNA expression of other BMP/SMAD target genes is unaltered. To identify the mechanism through which hepatic lipid accumulation causes “iron resistance”, we established an in vitro model of steatosis: Huh-7 cells treated with palmitic and oleic acids become “steatotic”. In this model, the overall TfR1 protein levels are unchanged, but its cell surface expression is increased. Despite this, the binding affinity of TfR1 for transferrin is reduced. These results suggest that steatosis affects TfR1 function thus causing iron resistance, suggesting a new role for TfR1 in mediating increased systemic iron levels in T2DM patients.
We have previously demonstrated that T2DM patients show inappropriately low hepcidin levels despite increased systemic iron. Analysis of the db/db mouse model of T2DM further showed an “iron resistance” phenotype, whereby the steatotic liver is iron deficient in the presence of increased plasma iron levels.
We now aim to identify the mechanism(s) how T2DM causes hepatic iron resistance. We excluded hyperglycaemia and reduced insulin-related signalling, since iron-parameters remained unaltered in non-obese insulin-deficient Ins2(Akita) mice. We next generated the western diet-induced model of NAFLD. These mice show normoglycemia and unaltered expression of key genes involved in glycolysis and gluconeogenesis compared to wild-type mice. In this model, the liver is steatotic and iron deficient while plasma iron levels are elevated, mirroring T2DM. Hepcidin mRNA expression is strongly decreased even though mRNA expression of other BMP/SMAD target genes is unaltered. To identify the mechanism through which hepatic lipid accumulation causes “iron resistance”, we established an in vitro model of steatosis: Huh-7 cells treated with palmitic and oleic acids become “steatotic”. In this model, the overall TfR1 protein levels are unchanged, but its cell surface expression is increased. Despite this, the binding affinity of TfR1 for transferrin is reduced. These results suggest that steatosis affects TfR1 function thus causing iron resistance, suggesting a new role for TfR1 in mediating increased systemic iron levels in T2DM patients.