Inflammation-induced TRIM21 represses hepatic steatosis by promoting the ubiquitination of lipogenic regulators
Kostas C. Nikolaou, Svenja Godbersen, Muthiah Manoharan, Stefan Wieland, Markus H. Heim, Markus Stoffel
Kostas C. Nikolaou, Svenja Godbersen, Muthiah Manoharan, Stefan Wieland, Markus H. Heim, Markus Stoffel
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Research Article Hepatology

Inflammation-induced TRIM21 represses hepatic steatosis by promoting the ubiquitination of lipogenic regulators

Abstract

Nonalcoholic steatohepatitis (NASH) is a leading cause for chronic liver diseases. Current therapeutic options are limited due to an incomplete mechanistic understanding of how steatosis transitions to NASH. Here we show that the TRIM21 E3 ubiquitin ligase is induced by the synergistic actions of proinflammatory TNF-α and fatty acids in livers of humans and mice with NASH. TRIM21 ubiquitinates and degrades ChREBP, SREBP1, ACC1, and FASN, key regulators of de novo lipogenesis, and A1CF, an alternative splicing regulator of the high-activity ketohexokinase-C (KHK-C) isoform and rate-limiting enzyme of fructose metabolism. TRIM21-mediated degradation of these lipogenic activators improved steatosis and hyperglycemia as well as fructose and glucose tolerance. Our 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. Thus, enhancing this natural counteracting force of steatosis through inhibition of key lipogenic activators via TRIM21-mediated ubiquitination may provide a therapeutic opportunity to treat NASH.

Authors

Kostas C. Nikolaou, Svenja Godbersen, Muthiah Manoharan, Stefan Wieland, Markus H. Heim, Markus Stoffel

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Figure 4

Hepatic TRIM21 protects from fructose-induced steatosis via degradation of A1CF.

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Hepatic TRIM21 protects from fructose-induced steatosis via degradation ...
(A) Levels of total and K63-linked endogenous A1CF ubiquitination and input protein expression in liver extracts of Ad-Trim21 or Ad-Ctrl C57BL/6N mice fed a HFru diet for 4 weeks (n = 3 mice per group). (B–H) Random plasma blood glucose (B), plasma insulin levels (C), liver weight (D), liver triglyceride (TG) (E), plasma TG (F), fructose-tolerance test (3 g/kg fructose) (G), and relative hepatic mRNA expression of indicated genes (n = 7 mice per group) (H) from mice indicated as in A. (I) Western blot analysis of indicated proteins in livers of GalNAc-siA1cf and control injected 12-week-old C57BL/6N mice fed HFru diet for 4 weeks (n = 3 mice/group). (J) Blood glucose from C57BL/6N control mice fed a normal diet (ND) or GalNAc-siA1cf–injected and control mice fed a HFru diet for 4 weeks. (K–P) Plasma insulin (K), plasma TG (L), hepatic TG levels (M), liver weight (N), fructose tolerance test (3 g/kg Fru) (O), (blue asterisks. ND versus HFru diet control; black, ND versus HFru GalNAc-siA1cf; red asterisks, HFru control versus HFru GalNAc-siA1cf) and relative hepatic mRNA expression of indicated metabolic genes (P) from mice indicated as in J. Mice per group for B–G: Ad-Ctrl (n = 7), Ad-Trim21 (n = 8); for J–P: ND (n = 5), controls or GalNAc-siA1cf in HFru diet group (n = 6 each). n represents number of replicates, 1 mouse/replicate. In all statistical plots, data are expressed as mean ± SD; ****P < 0.0001; ***P < 0.001; **P < 0.01; *P < 0.05. Statistical analysis for B, G, J, and O was carried out by 2-way ANOVA with Sidak’s post hoc analysis; for C–F and H by t test; and for K–N and P by 1-way ANOVA with Sidak’s post hoc analysis.