Intracellular retention of hepatic serpins caused by severe hyperlipidemia.
BACKGROUND
High levels of circulating lipids contribute to both the development of non-alcoholic liver steatosis (NALS) and peripheral arterial disease, leading to increased thrombotic risk. However, the effects of hyperlipidemia on hepatic proteins have barely been studied. Antithrombin is a hepatic serpin with anticoagulant and anti-inflammatory roles. The conformational flexibility of antithrombin renders it susceptible to both, genetic and posttranslational modifications. Thus, mutations and environmental factors have been shown to alter this molecule.


METHODS
We used a chick model to assess the effects of hyperlipidemic diets (HD) on this conformationally sensitive molecule. We determined antithrombin activity in plasma and evaluated the histological and immunohistological features of livers from these animals.


RESULTS
A HD for 6 months led to a significant intrahepatic retention and aggregation of antithrombin, which correlated with hepatic steatosis, as revealed by immunohistological analysis. Accordingly, a decrease in circulating antithrombin activity (48.71 +/- 6.35%) was observed. Other hepatic proteins, including heparin cofactor II, another anticoagulant serpin, also accumulated intracellularly. Atorvastatin and reversion to a normal diet after 3 months partially protected livers from these deleterious effects.


CONCLUSIONS
Our results support that hyperlipidemia-induced NALS causes a significant intracellular aggregation of hemostatic serpins in liver, which determines a decrease in their circulating levels.
Hernández-Espinosa
David
D
Department of Medicine, Centro Regional de Hemodonación, University of Murcia, Murcia, Spain.
Ayala
Ignacio
I
Castells
Maria Teresa
MT
García-Pérez
Bartolomé
B
Martín-Castillo
Antonia
A
Miñano
Antonia
A
Arcas
Isabel
I
Vicente
Vicente
V
Corral
Javier
J
D000818:Animals; D000991:Antithrombins / Q000378:metabolism; D000069059:Atorvastatin; D002645:Chickens; D004041:Dietary Fats / Q000008:administration & dosage; D004195:Disease Models, Animal; D065427:Factor Xa Inhibitors; D005234:Fatty Liver / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D015844:Heparin Cofactor II / Q000378:metabolism; D006538:Heptanoic Acids / Q000627:therapeutic use; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use; D006949:Hyperlipidemias / Q000150:complications / Q000188:drug therapy / Q000378:metabolism*; D007424:Intracellular Fluid / Q000378:metabolism; D050356:Lipid Metabolism; D008055:Lipids / Q000097:blood; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008297:Male; D011758:Pyrroles / Q000627:therapeutic use; D015843:Serpins / Q000378:metabolism*
D000991:Antithrombins; D004041:Dietary Fats; D065427:Factor Xa Inhibitors; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008055:Lipids; D011758:Pyrroles; D015843:Serpins; D015844:Heparin Cofactor II; D000069059:Atorvastatin