Human FASN adenoviral particles

Disturbances in hepatic glucose and lipid metabolism promote the development and progression of type 2 diabetes mellitus (T2DM), but the underlying mechanisms are not fully understood. Here, researchers identify for the first time the class IV TRIM family member tripartite motif-containing protein 21 (TRIM21) as a key regulator of hepatic metabolism in T2DM. Bioinformatics analysis showed that TRIM21 expression was significantly reduced in patients with T2DM. Interestingly, in an obese diabetic mouse model, TRIM21 expression was primarily reduced in the liver, but not in other metabolic organs. Researchers further demonstrated that hepatic overexpression of TRIM21 significantly improved glucose intolerance, insulin resistance, hepatic steatosis, and dyslipidemia in obese diabetic mice. Mechanistically, both phosphoenolpyruvate carboxykinase 1 (PEPCK1) and fatty acid synthase (FASN) are hepatic targets of TRIM21. Researchers found that TRIM21 promotes the degradation of PEPCK1 and FASN via K48-linked ubiquitination mediated by direct protein-protein interactions. Notably, overexpression of PEPCK1 and FASN substantially abolished the beneficial effects of TRIM21 overexpression in obese diabetic mice. Altogether, these data indicate that TRIM21 is a novel regulator of hepatic metabolic disorders and suggest that TRIM21 is a promising therapeutic target for type 2 diabetes.

To investigate whether PEPCK1 and FASN are involved in the inhibitory effect of TRIM21 on hepatic glucose and lipid metabolism disorders, adenovirus-PEPCK1 (Ad-PEPCK1) and/or adenovirus-FASN (Ad-FASN) were injected into HFD-fed mice overexpressing TRIM21. The protective effect of TRIM21 overexpression against HFD-induced glucose intolerance and insulin resistance was partially abolished by PEPCK1 or FASN overexpression (Figure 1a, b). Notably, the reversal effect of PEPCK1 and FASN overexpression was more significant. The area under the curve (AUC) of GTT and ITT was also increased in PEPCK1 or FASN overexpressing mice (Figure 1a, b). PEPCK1 and/or FASN overexpression also partially reversed the hepatic TG levels and serum TG suppression in TRIM21 overexpressing mice on a HFD diet (Figure 1c, d). Ectopic TRIM21 expression consistently attenuated intracellular TG accumulation in mouse primary hepatocytes exposed to a combination of palmitic acid and oleic acid, whereas overexpression of PEPCK1 and/or FASN reversed this phenomenon (Figure 1e). These results suggest that TRIM21 suppresses hepatic glucose and lipid metabolism disorders by regulating PEPCK1 and FASN expression.

Figure 1. TRIM21 suppressed hepatic glucose and lipid metabolic disorders by regulating PEPCK1 and FASN expression. (Zhang K, et al., 2023)