A high-fat and cholesterol diet causes fatty liver in guinea pigs. The role of iron and oxidative damage

Abstract

Non-alcoholic fatty liver disease (NAFLD) is a common chronic liver disease. Iron, cholesterol, and oxidative damage are frequently suggested to be related to the progression of NAFLD, but the precise relationship between them remains unclear. Guinea pigs fed on a high cholesterol and fat diet (without oxidized lipids) generated a disease model of NAFLD with hallmark observations in liver histology and increased liver damage markers. Hepatic cholesterol and iron levels were found to be significantly elevated and directly correlated. Plasma hepcidin and transferrin levels were decreased. Plasma iron concentrations were found to be elevated, likely due to an increased intestinal iron absorption caused by the decrease in plasma hepcidin. However, hepatic transferrin receptor-2 levels were unchanged. No significant increase in hepatic lipid peroxidation was detected using F2-isoprostanes as a reliable biomarker, nor was there a rise in protein carbonyls, a general index of oxidative protein damage. Some increases in cholesterol oxidation products were observed, but largely negated after normalizing for the elevated hepatic cholesterol content. Indeed, increased hemosiderin deposition and unchanged ferritin levels in liver suggested that the excess iron mainly existed as hemosiderin, which is redox-inactive.

Normal weight dyslipidemia: Is it all about the liver?

“…Therefore, the guinea pig may be a more appropriate model in these regards . Indeed, guinea pigs fed a high‐fat diet supplemented with cholesterol developed dyslipidemia with enhanced LDL‐C concentrations, and NAFLD was confirmed by hepatic steatosis and inflammation . With increased dietary cholesterol, hepatic fibrosis was also induced, hereby demonstrating the model's ability to mimic human dyslipidemia and evolving hepatic damage including progression from NAFLD to NASH .…”

“…Indeed, guinea pigs fed a high‐fat diet supplemented with cholesterol developed dyslipidemia with enhanced LDL‐C concentrations, and NAFLD was confirmed by hepatic steatosis and inflammation . With increased dietary cholesterol, hepatic fibrosis was also induced, hereby demonstrating the model's ability to mimic human dyslipidemia and evolving hepatic damage including progression from NAFLD to NASH . Currently, no single experimental model recapitulates the dyslipidemic and metabolic profile of human NAFLD, highlighting the necessity of investigating novel approaches to increase animal model validity and translational value in the quest for elucidating the etiology and treatment of this complex disease.…”

The Potential of Non-Provitamin A Carotenoids for the Prevention and Treatment of Non-Alcoholic Fatty Liver Disease

“…This leads to the development of insulin resistance and the generation of reactive oxygen species (ROS) [16]. Although normal hepatic metabolism produces ROS, external factors also generate oxidative stress [14,17]. These ROS can induce lipid peroxidation and the disruption of proteins and DNA.…”

Hepcidin: Homeostasis and Diseases Related to Iron Metabolism

“…In an animal model with non-alcoholic fatty liver disease suggested by Ye et al [118], serum hepcidin levels decreased with hepatic injury, increased iron and free cholesterol, and haemosiderin deposition in hepatocytes, with no change in transferrin receptors. Decreased hepcidin synthesis leads to impairment of the pathogenesis of alcoholic cirrhosis and autoimmune hepatitis, with increased production of hydrogen peroxide in which alcohol functions as negative regulator of hepcidin [119,120,121,122,123].…”