Cadre's Ward, The Fourth Clinical College of Xinjiang Medical University, Urumqi, 830000, Xinjiang Uygur Autonomous Region, China.
Department of Neurology, Urumqi Midong District Hospital of Traditional Chinese Medicine, Urumqi, 830000, Xinjiang Uygur Autonomous Region, China.
J Endocrinol Invest. 2024 Nov;47(11):2757-2774. doi: 10.1007/s40618-024-02376-5. Epub 2024 May 2.
Hyperlipidemia is a lipid metabolism disorder with increasing incidence and prevalence worldwide. Abnormal lipid metabolism and inflammation are two significant characteristics of hyperlipidemia. The purpose of this study was to explore the role and mechanism of F-box only protein 28 (FBXO28) in hyperlipidemia.
Mice were fed with high-fat diet (HFD) to elicit obesity, and 3T3-L1 preadipocytes were stimulated with MDI cocktail (IBMX, DEX and insulin) to evoke differentiation. In vivo and in vitro role of FBXO28 in hyperlipidemia was investigated by hematoxylin-eosin and oil Red O staining, the lipid biochemistry measurement, enzyme-linked immunosorbent assay, reverse transcription quantitative polymerase chain reaction and western blotting assays. The mechanism of FBXO28 explored by co-immunoprecipitation, immunofluorescence, ubiquitination and cycloheximide assays.
Low expression of FBXO28 was found in hyperlipidemia in silico, in vivo and in vitro. Upregulation of FBXO28 declined the body weight, fat accumulation, and serum lipid content in HFD-fed mice. Abnormal lipid accumulation, and the level of liposynthetic genes and beta-oxidation related genes were improved by overexpression of FBXO28 both in HFD-elicited mice and MDI-treated 3T3-L1 preadipocytes. Besides, overexpression of FBXO28 declined HFD-induced the level of proinflammatory factors and F4/80. Mechanically, FBXO28 directly bound RAB27A and promoted its ubiquitinated degradation. Thus, upregulation of RAB27A inverted the improved role of FBXO28 in abnormal lipid metabolism and inflammation in vivo and in vitro.
FBXO28 ameliorated abnormal lipid metabolism and inflammation through the ubiquitinated degradation of RAB27A, thereby attenuating HFD-induced hyperlipidemia. The results could promote the treatment of hyperlipidemia, and the relevant diseases.
高脂血症是一种脂质代谢紊乱疾病，其发病率和患病率在全球范围内呈上升趋势。异常的脂质代谢和炎症是高脂血症的两个重要特征。本研究旨在探讨 F-box 仅蛋白 28（FBXO28）在高脂血症中的作用和机制。
用高脂肪饮食（HFD）喂养小鼠诱发肥胖，用 MDI 鸡尾酒（IBMX、DEX 和胰岛素）刺激 3T3-L1 前脂肪细胞诱导分化。通过苏木精-伊红和油红 O 染色、脂质生化测定、酶联免疫吸附试验、逆转录定量聚合酶链反应和 Western blot 分析，研究 FBXO28 在体内和体外高脂血症中的作用。通过免疫共沉淀、免疫荧光、泛素化和环己酰亚胺试验探讨 FBXO28 的作用机制。
在高脂血症的计算机模拟、体内和体外研究中，均发现 FBXO28 的表达水平较低。FBXO28 的上调降低了 HFD 喂养小鼠的体重、脂肪堆积和血清脂质含量。在 HFD 诱发的小鼠和 MDI 处理的 3T3-L1 前脂肪细胞中，FBXO28 的过表达改善了异常脂质堆积和脂肪合成基因及β氧化相关基因的水平。此外，FBXO28 的过表达降低了 HFD 诱导的促炎因子和 F4/80 的水平。机制上，FBXO28 直接与 RAB27A 结合，并促进其泛素化降解。因此，上调 RAB27A 逆转了 FBXO28 在体内和体外改善异常脂质代谢和炎症的作用。
FBXO28 通过 RAB27A 的泛素化降解改善异常脂质代谢和炎症，从而减轻 HFD 诱导的高脂血症。研究结果为高脂血症及相关疾病的治疗提供了新的思路。
