Loss of energy homeostasis contributes to hepatic damage development in sickle cell disease

TL;DR

This study explores how energy imbalance in the liver contributes to liver damage in sickle cell disease.

Contribution

The study reveals a previously unknown link between energy homeostasis disruption and liver damage in sickle cell disease.

Findings

SCD mice show iron overload and liver ischemia, leading to inflammation and tissue damage.

Energetic impairment in SCD livers is linked to mitochondrial dysfunction and oxidative stress.

Lipid metabolism changes and foam cell accumulation are observed in SCD mouse livers.

Abstract

Sickle cell disease (SCD) is characterized by the expression of an abnormal hemoglobin variant (HbS) that promotes distortion and early destruction of red blood cells, resulting in hemolytic anemia, vaso-occlusive crisis, ischemia and, ultimately, tissue damage. Hepatic function is specially compromised in SCD patients; however, the underlying pathological mechanisms remain largely unknown. In the current study, we confirmed the presence of hepatic damage in a murine model of SCD and, through a label free quantitative proteomic approach, we identified significant alterations in protein expression compared to healthy controls. These changes unveiled distinct proteome expression profiles between groups, with molecular alterations linked to impaired hepatic function, anemia, mitochondrial dysfunction, and alteration in lipid metabolism. We also confirmed these novel alterations through molecular and functional analyses, revealing a previously undescribed liver energy homeostasis imbalance, accompanied by accumulation of foam cells. Our findings provide new insights into the complex mechanisms underlying liver disease and potential therapeutic targets in SCD.

Image 1

•SCD mice suffer from iron overload and recurrent ischemic events in the liver, fostering inflammation and tissue damage.•In the SCD liver, energetic impairment is exacerbated and coincides with mitochondrial dysfunction and oxidative stress.•Alterations in lipid metabolism and foam cell accumulation are detected in the liver of SCD mice.

SCD mice suffer from iron overload and recurrent ischemic events in the liver, fostering inflammation and tissue damage.

In the SCD liver, energetic impairment is exacerbated and coincides with mitochondrial dysfunction and oxidative stress.

Alterations in lipid metabolism and foam cell accumulation are detected in the liver of SCD mice.

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