Rbks plays a novel role in maintaining glycolipid metabolic homeostasis.

Abstract

Elevated urinary D-ribose has been observed in patients with diabetes and Alzheimer's disease, although the underlying mechanism remains unclear. Since ribokinase (Rbks) catalyzes the phosphorylation of D-ribose to ribose-5-phosphate, we hypothesize that the Rbks gene plays a crucial role in regulating systemic glucose and lipid metabolism. To test this hypothesis, we generate Rbks-knockout (KO) C57BL/6J mice using CRISPR/Cas9 and conduct a 16-week phenotypic observation. Although KO mice exhibit normal physical appearance and body weight, they show reduced food consumption and water intake. Serum levels of total cholesterol (T-CHO) and low-density lipoprotein cholesterol (LDL-C) are decreased, accompanied by hepatic accumulation of T-CHO. Proteomic analysis identifies 117 differentially expressed proteins associated with glycolipid metabolism and oxidative phosphorylation. Metabolomic profiling reveals 414 altered metabolites enrich in lipid metabolism, central carbon metabolism, and amino acid metabolism pathways. Among these alterations, the most prominent change is enhanced hepatic cholesterol and bile acid (BA) synthesis, which is supported by elevated hepatic T-CHO levels and increased mRNA expressions of 3-hydroxy-3-methylglutaryl-CoA reductase ( Hmgcr) and squalene epoxidase ( Sqle). This study reveals a novel role for Rbks in maintaining glucose-lipid metabolic homeostasis, especially with potential implications for understanding metabolic disorders characterized by altered cholesterol flux.