Novel targets of β‐TrCP cooperatively accelerate carbohydrate and fatty acid consumption

Abstract

Cellular energy is primarily produced from glucose and fat through glycolysis and fatty acid oxidation (FAO) followed by the tricarboxylic acid cycle in mitochondria; energy homeostasis is carefully maintained via numerous feedback pathways. In this report, we uncovered a new master regulator of carbohydrate and lipid metabolism. When ubiquitin E3 ligase β‐TrCP2 was inducibly knocked out in β‐TrCP1 knockout adult mice, the resulting double knockout mice (DKO) lost fat mass rapidly. Biochemical analyses of the tissues and cells from β‐TrCP2 KO and DKO mice revealed that glycolysis, FAO, and lipolysis were dramatically upregulated. The absence of β‐TrCP2 increased the protein stability of metabolic rate‐limiting enzymes including 6‐phosphofructo‐2‐kinase/fructose‐2,6‐bisphosphatase (PFKFB3), adipose triglyceride lipase (ATGL), carnitine palmitoyltransferase 1A (CPT1A), and carnitine/acylcarnitine translocase (CACT). Our data suggest that β‐TrCP is a potential regulator for total energy homeostasis by simultaneously controlling glucose and fatty acid metabolism and that targeting β‐TrCP could be an effective strategy to treat obesity and other metabolic disorders.

Protein modifications and diseases

“…This special issue also includes original research articles to identify new targets of protein SUMOylation and ubiquitination (Chen et al, 2023; Joo et al, 2023). Chen et al (2023) produced a monoclonal SUMO1C‐K antibody recognizing SUMOylated peptides.…”

“…This study provides a strategy to identify wild‐type SUMO1‐modification sites (Chen et al, 2023). Moreover, Joo et al (2023) uncovered ubiquitin E3 ligase β‐TrCP2 as a new master regulator of carbohydrate and lipid metabolism. Impressively, a double knockout (KO) mice model that inducible knocked out ubiquitin E3 ligase β‐TrCP2 in β‐TrCP1 KO adult mice, resulting fast lost fat mass in vivo (Joo et al, 2023).…”

“…Moreover, Joo et al (2023) uncovered ubiquitin E3 ligase β‐TrCP2 as a new master regulator of carbohydrate and lipid metabolism. Impressively, a double knockout (KO) mice model that inducible knocked out ubiquitin E3 ligase β‐TrCP2 in β‐TrCP1 KO adult mice, resulting fast lost fat mass in vivo (Joo et al, 2023). Loss of β‐TrCP2 increased the protein stability of several metabolic rate‐limiting enzymes including PFKFB3, ATGL, CPT1A, and CACT, suggesting targeting β‐TrCP as a potential strategy to treat metabolic disorders (Joo et al, 2023).…”