| Description |
Non-Alcoholic Fatty Liver Disease (NAFLD) is characterized by the accumulation of fat in the liver, which causes hepatic inflammation, fibrosis, and scarring. This scarring results in decreased liver function, such as hepatic encephalopathy and hepatorenal failure. NAFLD is found in approximately 30% of adults in the U.S. and is the leading cause of liver transplants worldwide. The causes of NAFLD are not well understood. Previous research has found some connection between a high-fat diet or iron overload (from genetic conditions such as hemochromatosis) and NAFLD. Many NAFLD cases, however, feature iron deficiency in contrast to iron overload, suggesting that maintaining a balance of iron is essential for healthy liver function. The mitochondria are an important part of this balancing act by serving as both a center for heme and Fe-S synthesis as well as the β-oxidation of fatty acids. Iron delivery into the mitochondria is essential for Fe-S and heme synthesis and controlling iron levels in the mitochondria is essential to maintaining fat metabolism in the liver. Two mitochondrial iron importers Mitoferrin 1 (Mfrn1) and Mitoferrin 2 (Mfrn2) have been identified. Mfrn1 is essential for erythropoiesis, but a role for Mfrn2 is unknown. Mice with a full body knockout of Mfrn2 show increased liver triglycerides, and when placed on a low iron diet, liver triglyceride levels rise dramatically. Liver cholesterol levels are also elevated in the absence of Mfrn2. Serum triglyceride and cholesterol levels are not elevated. Wild type animals also show increased liver triglycerides when placed on a low iron diet, and iv lipidomic analyses show dramatic shifts in response to both the low iron diet and to loss of Mfrn2. These changes include increased levels of long chain fatty acids, alterations in phosphorylcholine, elevated levels of diacylglycerol, and ceramide. These lipid changes are indicative of increased hepatic inflammation, and Mfrn2 null animals show increased serum ferritin levels that are exacerbated by the low iron diet. Further, Mfrn2 null animals show increased alanine aminotransferase levels, which is indicative of increased liver damage. These changes in lipid metabolism are specific to the total body loss of Mfrn2 and are not due to loss of Mfrn2 in hepatocytes or adipocytes. Liver gene expression analysis reveals increased expression of the fatty acid uptake gene CD36 as well as increased expression of fatty acid synthase (Fasn). Loss of Mfrn2 also gives rise to alterations in lipid signature in the serum, which may provide a diagnostic profile for the early detection of NAFLD. These results support that mitochondrial iron import through Mfrn2 is important for lipid homeostasis in the liver. This project focuses on understanding how the loss of Mfrn2 and iron deficiency play a role in NAFLD. |
