TSH attenuates fatty acid oxidation in hepatocytes by reducing the mitochondrial distribution of miR-449a/449b-5p/5194

Abstract

The elevated thyroid-stimulating hormone (TSH) levels contribute to the abnormal expression/activity of several key hepatic lipid metabolism enzymes. Although miRNAs have been shown to play key roles in hepatic lipid metabolism and are found in isolated mitochondria, very little is known about the pathological and physiological significance of their mitochondrial distributions in regulating liver lipid metabolism. Here, we found that TSH significantly reduced the distribution of some miRNAs in mitochondria of hepatocytes, especially miR-449a, miR-449b-5p, and miR-5194. These three miRNAs inhibited their target genes PGC1B, ABCD1, ADIPOR1 and the downstream molecule PPARA. These effects synergistically suppressed fatty acid (FA) β-oxidation in mitochondria and peroxisomes and decreased the translocation of cytosolic very long chain fatty acids to peroxisomes, which noticeably reduced FA catabolism and promoted triglyceride accumulation in hepatocytes. This study reveals the functional significance of changed miRNA mitochondrial-cytoplasmic distribution in the regulation of hepatic lipid metabolism.