Knockdown of LOX-1 ameliorates bone quality and generation of type H blood vessels in diabetic mice.

Our previous studies have shown that lectin-like oxidized low-density lipoprotein receptor 1 (LOX-1) is expressed in liver sinusoidal endothelial cells, and oxidized low-density lipoprotein induces liver sinusoidal dysfunction and defenestration through the LOX-1/ROS/NF-kB pathway, revealing that LOX-1 can mediate liver sinusoidal barrier function, involved in the regulation of non-alcoholic fatty liver disease. Here, we investigated whether, in the context of bone metabolic diseases, LOX-1 could affect bone quality and type H blood vessels in diabetic mice. We used db/db mice as model and found that LOX-1 knockdown can ameliorate bone quality and type H blood vessel generation in db/db mice. This further verifies our hypothesis that LOX-1 is involved in the regulation of bone quality and type H blood vessel homeostasis, thus inhibiting osteoporosis progression in db/db mice.

LOX-1 attenuates high glucose-induced autophagy via AMPK/HNF4α signaling in HLSECs.

Type 2 diabetes mellitus (T2DM) combined with nonalcoholic fatty liver disease (NAFLD) is a common cause of death. Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is involved in the regulation of autophagy and associated with a variety of diseases, such as atherosclerosis, diabetes, and NAFLD. This study aimed to investigate the effect of LOX-1 on autophagy induced by high glucose levels in human liver sinusoidal endothelial cells (HLSECs) and whether it regulates autophagy through the adenosine monophosphate-activated protein kinase/hepatocyte nuclear factor 4α (AMPK/HNF4α) pathway. In this study, HLSECs cultured with high glucose medium showed increased expression of LOX-1, whereas autophagy was inhibited. High glucose levels decreased the AMPK phosphorylation, increased the HNF4α phosphorylation, and retained the HNF4α in the cytoplasm. By contrast, silencing of LOX-1 reversed the phenomenon induced by high glucose levels and restored the HNF4a localization. Taken together, our findings reveal a novel mechanism of high glucose-induced autophagy in HLSECs, namely, the LOX-1-mediated AMPK/HNF4α signaling pathway. Therefore, LOX-1 is an important target molecule for the regulation of autophagy in HLSECs.