7885 Thyroid Hormone Stimulates Heaptic Lipid Metabolism in the Resolution of Liver Fibrosis
Authors: Mendoza A , Wang C , Lugo A , Rodrigues V , Houghton S , Redmond D , Hollenberg A 
Published: October 2024

Disclosure: A. Mendoza: None. C. Wang: None. A. Lugo: None. V. Rodrigues: None. S. Houghton: None. D. Redmond: None. A. Hollenberg: None.

Metabolic dysfunction-associated steatotic liver disease (MASLD) progression to steatohepatitis and fibrosis is a global health burden, leading to liver failure and death. While the pathogenesis is complex, dysregulated lipid metabolism plays a crucial role. Thyroid hormones (THs) are key metabolic regulators in the liver, promoting lipogenesis and fatty acid oxidation. Previously, we demonstrated that the carbohydrate-responsive element binding protein (ChREBP) is a critical mediator of both these processes in hepatocytes, acting downstream of the thyroid hormone receptor beta1 (TRβ1). Interestingly, while ChREBP ablation abolished TH-induced lipogenesis through downregulation of lipogenic gene expression, its role in TH-mediated fatty acid oxidation remained unclear, suggesting a multifaceted role for ChREBP in TH-regulated hepatic metabolism. Given the critical role of lipid metabolism in the progression of MASLD to metabolic dysfunction-associated steatohepatitis (MASH) and fibrosis, we aim to delineate the mechanisms by which TH promotes the regression of fibrosis. Here, we used a carbon tetrachloride (CCL4) model of liver fibrosis in TRβ1KO and ChREBPKO mice (0.4 ul/g biweekly, 9 injections). All mice in the experiments were also on a PTU-Low Iodine diet to induce hypothyroidism. In the last week of the protocol, all mice were sorted into two groups which received either water or T3 (1ug/ml). 24 hours after the last CCL4 injection all mice were sacrificed and the livers were harvested and prepared for analysis. Herein we show that T3 promotes the resolution of liver fibrosis in wild-type mice. Importantly, this resolution was abolished in both TRβ1 and ChREBP KO mice demonstrating this pathways essential role in TH-induced resolution of fibrosis. RNA-Seq analysis of TRβ1KO mice demonstrated a dual mechanism of TH action: 1. TH upregulates gene expression in multiple metabolic pathways, suggesting a rescue of hepatic metabolism towards normal liver function and 2., TH has antifibrotic action via downregulation of pathways controlling extracellular matrix synthesis and inflammation, key drivers of fibrosis. Strikingly, ChREBP was dispensable for the antifibrotic action of TH suggesting that the ChREBP-dependent regulation of hepatic metabolism is critical for the resolution of fibrosis mediated by TH. To identify novel metabolic pathways regulated by TH via ChREBP, we intersected liver mRNA-seq from TRβ1KO mice with liver-specific ChREBP Chip-Seq and identifed multiple targets regulating autophagy that require ChREBP for their activation after TH treatment. These data suggest that the ability of ChREBP to regulate TH-induced fatty-acid oxidation is mediated by the upregulation of autophagy. This supports the notion that the ability of T3 to promote the resolution of liver fibrosis is primarily dependent of it’s ability to stimulate hepatic fatty acid metabolism.

Presentation: 6/1/2024