Department of Pharmacology and Toxicology and Brown Cancer Center, University of Louisville School of Medicine, Louisville, KY, 40202, USA.
Environmental Justice, Community Health and Environmental Review Division, US Environmental Protection Agency, Chicago, USA.
Cardiovasc Toxicol. 2024 Aug;24(8):747-756. doi: 10.1007/s12012-024-09874-1. Epub 2024 Jun 8.
Metabolic dysfunction associated-steatotic liver disease (MASLD)/metabolic dysfunction-associated steatohepatitis (MASH) is the liver manifestation of metabolic syndrome, which is characterized by insulin resistance, hyperglycemia, hypertension, dyslipidemia, and/or obesity. Environmental pollutant exposure has been recently identified as a risk factor for developing MASH. Heterocyclic amines (HCAs) are mutagens generated when cooking meat at high temperatures or until well-done. Recent epidemiological studies reported that dietary HCA exposure may be linked to insulin resistance and type II diabetes, and we recently reported that HCAs induce insulin resistance and glucose production in human hepatocytes. However, no previous studies have examined the effects of HCAs on hepatic lipid homeostasis. In the present study, we assessed the effects of two common HCAs, MeIQx (2-amino-3, 8-dimethylimidazo [4, 5-f] quinoxaline) and PhIP (2-amino-1-methyl-6-phenylimidazo[4, 5-b] pyridine), on lipid homeostasis in cryopreserved human hepatocytes. Exposure to a single concentration of 25 μM MeIQx or PhIP in human hepatocytes led to dysregulation of lipid homeostasis, typified by significant increases in lipid droplets and triglycerides. PhIP significantly increased expression of lipid droplet-associated genes, PNPLA3 and HSD17B13, and both HCAs significantly increased PLIN2. Exposure to MeIQx or PhIP also significantly increased expression of several key genes involved in lipid synthesis, transport and metabolism, including FASN, DGAT2, CPT1A, SCD, and CD36. Furthermore, both MeIQx and PhIP significantly increased intracellular cholesterol and decreased expression of PON1 which is involved in cholesterol efflux. Taken together, these results suggest that HCAs dysregulate lipid production, metabolism, and storage. The current study demonstrates, for the first time, that HCA exposure may lead to fat accumulation in hepatocytes, which may contribute to hepatic insulin resistance and MASH.
代谢功能障碍相关脂肪性肝病（MASLD）/代谢相关脂肪性肝炎（MASH）是代谢综合征的肝脏表现，其特征为胰岛素抵抗、高血糖、高血压、血脂异常和/或肥胖。环境污染物暴露最近被确定为发生 MASH 的一个危险因素。杂环胺（HCAs）是在高温或直至熟透烹饪肉类时产生的致突变物。最近的流行病学研究报告称，饮食中 HCA 暴露可能与胰岛素抵抗和 II 型糖尿病有关，我们最近报告称，HCAs 可诱导人肝细胞发生胰岛素抵抗和葡萄糖生成。然而，以前没有研究检查过 HCAs 对肝脂质稳态的影响。在本研究中，我们评估了两种常见的 HCAs，MeIQx（2-氨基-3,8-二甲基咪唑[4,5-f]喹喔啉）和 PhIP（2-氨基-1-甲基-6-苯基咪唑[4,5-b]吡啶）对冷冻保存人肝细胞中脂质稳态的影响。在人肝细胞中暴露于 25 μM 单浓度 MeIQx 或 PhIP 会导致脂质稳态失调，其特征是脂滴和甘油三酯显著增加。PhIP 显著增加了脂滴相关基因 PNPLA3 和 HSD17B13 的表达，两种 HCA 均显著增加了 PLIN2 的表达。暴露于 MeIQx 或 PhIP 还显著增加了参与脂质合成、转运和代谢的几个关键基因的表达，包括 FASN、DGAT2、CPT1A、SCD 和 CD36。此外，MeIQx 和 PhIP 均显著增加了细胞内胆固醇并降低了参与胆固醇外排的 PON1 的表达。综上所述，这些结果表明 HCAs 会扰乱脂质的产生、代谢和储存。本研究首次表明，HCA 暴露可能导致肝细胞内脂肪堆积，从而导致肝胰岛素抵抗和 MASH。
