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Selective mTORC1 inhibition prevents and treats NAFLD and NASH

ABSTRACT: We find that selective inhibition of one arm of mTORC1 signaling, via deletion of FLCN, promotes activation of the transcription factor TFE3 and profoundly protects against NAFLD and NASH in mice. (1) We performed genome-wide RNA-seq on livers from Control, liver-specific Flcn-null mice (LiFKO), and Flcn/Tfe3 double knock-out (DKO) mice fed either normal chow (NC) or a NAFLD-inducing diet (AMLN). We find TFE3-mediated induction of lysosomal and mitochondrial gene programs, and also suppression of de novo lipogenesis genes. (2) To understand whether TFE3 directly affects gene expression, we performed TFE3 ChIP-seq on livers from Control and LiFKO mice on normal chow. We find TFE3 occupancy on the chromatin at lysosomal genes, Ppargc1a (a driver of mitochondrial genes), and at de novo lipogenesis genes. (3) Finally, we wanted to test whether TFE3 antagonistically competes with the pro-lipogenic transcription factor SREBP-1c on chromatin. We therefore injected HA-tagged constitutively nuclear (active) SREBP-1c (nSREBP-1c), or a control virus, into control and LiFKO mice, treated them with a NAFLD-inducing diet (FPC diet), and collected liver tissue. We consequently performed HA-nSREBP-1c and TFE3 ChIP-seq experiments and observed no evidence of antagonistic competition.

ORGANISM(S): Mus musculus

PROVIDER: GSE160292 | GEO | 2022/04/15

REPOSITORIES: GEO

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Project description:Background and aim: The Insulin-like growth factor (IGF) axis is increasingly suggested to be involved in fatty liver disease and progression. We identified IGFBP2 as transcriptional regulatory effect network in liver steatosis and conducted a translational approach of its role in liver pathology from mouse to human, and whether it is influenced by conventional clinical intervention that mitigate hepatic steatosis. Methods: Primary hepatocytes from either C57Bl6 controls, alb-SREBP-1c mice with moderate transgene induced hepatic lipid accumulation or aP2-SREBP-1c mice with massive ectopic hepatic lipid accumulation, were analyzed to identify regulatory networks based on differentially regulated hepatic gene expression. In a translational approach, serum of morbidly obese patients with and without diabetes and biopsy-proven NAFLD were used for ELISA-based validation of mouse data. Moreover, sera of patients undergoing intervention were analyzed and correlated to liver fat content. Results: Comparative knowledge-based transcriptome analysis identified IGFBP2 as top score regulatory effect network between moderate and aggravated fatty liver in mouse models. The reduced expression of IGFBP2 in aP2-SREPB-1c progressed fatty liver associated with Igfbp2 promoter hypermethylation. Reduced secretion of IGFBP2 from aP2-SREBP-1c hepatocytes was reflected in the circulation of the animals. In this phenotype, reductions of IGFBP2 were accompanied by reduced fatty acid oxidation and increased methyltransferase and SIRT activity. Physiologically, IGFBP2 has no direct impact on lipid metabolism but might modulate IGF1 action on de novo lipogenesis. In humans, IGFBP2 levels declined from non-obese men to morbidly obese men with NAFLD and NASH. In intervention study reductions in liver fat correlated with restoration of IGFBP2 serum levels to values found in healthy individuals in morbidly obese patients following bariatric surgery. Conclusion: In hepatic metabolism changes of IGFBP2 abundance is connected to lipid metabolism whereas changes in IGFBP2 secretion were directly reflected in the circulation. IGFBP2 serum concentration correlates with the degree of fatty liver, which seems to be related to plasticity of the adipose tissue. These data provide IGFBP2 as a potential non-invasive biomarker for fatty liver disease directly reflecting the degree of impaired liver function with the potential to indicate progressed fatty liver disease.

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Selective mTORC1 inhibition prevents and treats NAFLD and NASH

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