Carnitine-acylcarnitine translocase is essential for oxidation of long-chain fatty acids in the liver

Abstract

Hepatic mitochondrial fatty acid oxidation (mFAO) is critical for maintaining systemic energy metabolism and carbon homeostasis. mFAO requires acyl-chains to be transported into the mitochondrial matrix in the form of acylcarnitines by carnitine acylcarnitine translocase (CACT). Unlike long-chain, medium-chain fatty acids do not require the acylcarnitine transport system for mitochondrial oxidative metabolism. While CACT is known as an essential component of mFAO, it is unknown if it’s a redundant enzyme, what its roles are in long- versus medium-chain fatty acid oxidation, and if it is required for liver health. To determine the roles and requirements for CACT we generated a novel conditional deletion mouse model targeting CACT specifically in hepatocytes, CactLiv-/-. Liver pathology, mitochondrial bioenergetics, and metabolite homeostasis were assessed under low-fat diet conditions and in response to high-fat, carbohydrate-free ketogenic diets containing either long-chain or medium-chain fatty acids. In the absence of liver CACT, the long-chain ketogenic diet increased circulating triglycerides and free fatty acids and caused severe hepatic steatosis after only 6 days of the diet. Indicators of liver metabolic stress were evident by increased expression of Fgf21 and Gdf15 in CactLiv-/- mice on the long-chain ketogenic diet. However, the medium-chain ketogenic diet did not induce metabolic stress genes or cause severe hepatic steatosis in CactLiv-/- mice. These data establish CACT as a critical determinant of long-chain fatty acid utilization and demonstrate that fatty acid chain length governs metabolic adaptation when mFAO is impaired.