N-end Rule–Mediated Proteasomal Degradation of ATGL Promotes Lipid Storage

Abstract

Cellular lipid storage is regulated by the balance of lipogenesis and lipolysis. The rate-limiting triglyceride hydrolase ATGL (desnutrin/PNPLA2) is critical for lipolysis. The control of ATGL transcription, localization and activation has been intensively studied, while regulation of the protein stability of ATGL is much less explored. Here we showed that the protein stability of ATGL is regulated by the N-end rule in cultured cells and in mice. The N-end rule E3 ligases UBR1 and UBR2 reduce the level of ATGL and affect lipid storage. The N-end rule-resistant ATGL(F2A) mutant, in which the N-terminal phenylalanine (F) of ATGL is substituted by alanine (A), has increased protein stability and enhanced lipolysis activity. ATGLF2A/F2A knock-in mice are protected against high-fat diet (HFD)-induced obesity, hepatic steatosis and insulin resistance. Hepatic knockdown of Ubr1 attenuates HFD-induced hepatic steatosis by enhancing the ATGL level. Finally, the protein levels of UBR1 and ATGL are negatively correlated in the adipose tissue of obese mice. Our study reveals N-end rule-mediated proteasomal regulation of ATGL, a finding which may potentially be beneficial for treatment of obesity.

Discovery and Development of Quinazolinones and Quinazolinediones for Ameliorating Nonalcoholic Fatty Liver Disease (NAFLD) by Modulating COP1-ATGL Axis

“…Moreover, adenovirus-mediated knockdown of COP1 could increase ATGL levels and ameliorate steatosis in HFD-fed mice. , Moreover, N-end rule pathway E3 ligases UBR1 and UBR2 modulated ATGL levels in liver. Knock-in mice with N-end rule-resistant mutation of ATGL (F2A) ( Atgl F2A/F2A ) exhibit enhanced lipolysis and were less susceptible to high fat-induced hepatic steatosis and obesity . E3 ligase peroxin2 (PEX2) also ubiquitinates ATGL.…”

“…Knock-in mice with N-end rule-resistant mutation of ATGL (F2A) (Atgl F2A/F2A ) exhibit enhanced lipolysis and were less susceptible to high fat-induced hepatic steatosis and obesity. 19 E3 ligase peroxin2 (PEX2) also ubiquitinates ATGL. Liverspecific mutation of PEX2 enhanced ATGL protein levels and its activity.…”