Published online Jul 28, 2023. doi: 10.3748/wjg.v29.i28.4433
Peer-review started: May 24, 2023
First decision: June 14, 2023
Revised: June 19, 2023
Accepted: July 11, 2023
Article in press: July 11, 2023
Published online: July 28, 2023
Processing time: 63 Days and 10.5 Hours
Non-alcoholic fatty liver disease (NAFLD) is a major health burden with an increasing global incidence. Unfortunately, the unavailability of knowledge underlying NAFLD pathogenesis inhibits effective preventive and therapeutic measures. The key issues affecting the treatment of patients with NAFLD are atherosclerotic cardio-cerebrovascular diseases, cirrhosis, and malignant tumors associated with the metabolic syndrome. The abnormal expression of F-box only protein 2 (FBXO2), an E3 ligase, in obese mice disrupts glucose homeostasis through ubiquitin-mediated insulin receptor degradation, however, the role of FBXO2 in NAFLD pathology remains unclear.
Recent studies conducted by our team found that the expression level of FBXO2 in NAFLD mouse models was downregulated after sleeve gastrectomy.
This study aimed to explore the molecular mechanism of NAFLD.
Whole genome sequencing (WGS) analysis was performed on liver tissues from patients with NAFLD (n = 6) and patients with normal metabolic conditions (n = 6) to identify the target genes. A NAFLD C57BL6/J mouse model induced by 16 wk of high-fat diet (HFD) feeding and a hepatocyte-specific FBXO2 overexpression mouse model were used for in vivo studies. Plasmid transfection, co-immunoprecipitation-based mass spectrometry assays, and ubiquitination in HepG2 cells and HEK293T cells were used for in vitro studies.
A total of 30982 genes were detected in WGS analysis, with 649 up-regulated and 178 down-regulated. Expression of FBXO2 was upregulated in the liver tissues of patients with NAFLD. Hepatocyte-specific FBXO2 overexpression facilitated NAFLD-associated phenotypes in mice. Overexpression of FBXO2 aggravated odium oleate (OA)-induced lipid accumulation in HepG2 cells, resulting in an abnormal expression of genes related to lipid metabolism, such as fatty acid synthase, peroxisome proliferator-activated receptor alpha, and so on. In contrast, knocking down FBXO2 in HepG2 cells significantly alleviated the oleate-induced lipid accumulation and aberrant expression of lipid metabolism genes. The hydroxyl CoA dehydrogenase alpha subunit (HADHA), a protein involved in oxidative stress, was a target of FBXO2-mediated ubiquitination. FBXO2 directly bound to HADHA and facilitated its proteasomal degradation in HepG2 and HEK293T cells. Supplementation with HADHA alleviated lipid accumulation caused by FBXO2 overexpression in HepG2 cells.
FBXO2 exacerbates lipid accumulation by targeting HADHA.
Our results shed light on the role of FBXO2 not only in NAFLD but also in other metabolic diseases involving lipid accumulation, supporting further investigation of the therapeutic potential of this molecule in further studies.