Int J Biol Sci 2021; 17(15):4108-4121. doi:10.7150/ijbs.64894 This issue

Research Paper

Systemic Deficiency of GHR in Pigs leads to Hepatic Steatosis via Negative Regulation of AHR Signaling

Qi Han1, Huiling Chen1, Likai Wang1, Yang An2, Xiaoxiang Hu1, Yaofeng Zhao1, Hao Zhang3, Ran Zhang1✉

1. State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, 100193, China.
2. MD Department of Plastic Surgery, Peking University Third Hospital, Beijing, 100191, China.
3. National Engineering Laboratory for Animal Breeding, China Agricultural University, Beijing, 100193, China.

This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.
Citation:
Han Q, Chen H, Wang L, An Y, Hu X, Zhao Y, Zhang H, Zhang R. Systemic Deficiency of GHR in Pigs leads to Hepatic Steatosis via Negative Regulation of AHR Signaling. Int J Biol Sci 2021; 17(15):4108-4121. doi:10.7150/ijbs.64894. Available from https://www.ijbs.com/v17p4108.htm

File import instruction

Abstract

Graphic abstract

Laron syndrome (LS) is an autosomal recessive genetic disease mainly caused by mutations in the human growth hormone receptor (GHR) gene. Previous studies have focused on Ghr mutant mice, but compared with LS patients, Ghr knockout (KO) mice exhibit differential lipid metabolism. To elucidate the relationship between GHR mutation and lipid metabolism, the role of GHR in lipid metabolism was examined in GHR KO pigs and hepatocytes transfected with siGHR. We observed high levels of free fatty acids and hepatic steatosis in GHR KO pigs, which recapitulates the abnormal lipid metabolism in LS patients. RNAseq analysis revealed that genes related to the fatty acid oxidation pathway were significantly altered in GHR KO pigs. AHR, a transcription factor related to lipid metabolism, was significantly downregulated in GHR KO pigs and siGHR-treated human hepatocytes. We found that AHR directly regulated fatty acid oxidation by directly binding to the promoters of ACOX1 and CPT1A and activating their expression. These data indicate that loss of GHR disturbs the ERK-AHR-ACOX1/CPT1A pathway and consequently leads to hepatic steatosis. Our results established AHR as a modulator of hepatic steatosis, thereby providing a therapeutic target for lipid metabolism disorder.

Keywords: Laron syndrome, GHR, hepatic steatosis, AHR