Inflammation-induced TRIM21 represses hepatic steatosis by promoting the ubiquitination of lipogenic regulators
A recent "Journal of Clinical Investigation" paper by the Stoffel group (IMHS) in collaboration with the Heim group (University Hospital Basel) demonstrates a novel role of the E3 ubiquitin ligase Trim21 in the control of fructose and lipid metabolism and the development of non-alcoholic steatohepatitis (NASH).
Nonalcoholic steatohepatitis (NASH) is a build-up of fat in the liver leading to inflammation and liver damage. It frequently develops in overweight people with diabetes, high blood cholesterol and triglyceride levels. Although a leading cause for chronic liver disease, current therapeutic options are limited due to an incomplete mechanistic understanding of how steatosis transitions to NASH.
Researchers at IMHS discovered that TRIM21, a E3 ubiquitin ligase, is activated by the synergistic actions of proinflammatory TNF-α and fatty acids in livers of humans and mice with NASH. TRIM21 degrades several key transcription factors, metabolic enzymes and alternative splicing regulators that are involved in lipid synthesis and fructose metabolism. TRIM21-mediated degradation of these lipogenic/fructolytic activators improved steatosis and hyperglycemia as well as fructose and glucose tolerance.
The study identifies TRIM21 as a negative regulator of liver steatosis in NASH and provides mechanistic insights into an immunometabolic crosstalk that limits fatty acid synthesis and fructose metabolism during metabolic stress. Enhancing this natural counteracting force of steatosis through inhibition of key lipogenic activators via TRIM21-mediated degradation may provide a therapeutic opportunity to treat NASH.
Link to the paper in external page "JCI".