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Retinoic Acid Receptor β Loss in Hepatocytes Increases Steatosis and Elevates the Integrated Stress Response in Alcohol-Associated Liver Disease

ABSTRACT: Background & Aims: Alcohol-associated liver disease (ALD) is associated with loss of vitamin A (retinoids), increased steatosis, and greater oxidative stress. Although a strong correlation has been observed between loss of retinoids and ALD, if retinoid loss plays a causal role in the pathophysiology of ALD is not clear. Approach & Results: Based on our prior published data indicating that a selective retinoic acid receptor beta (RARβ) agonist limits nonalcohol-related liver disease (NAFLD) pathology, we generated AlbCre;RARβ knockout (BKO) mice and fed these mice a Lieber DeCarli ethanol diet (ETOH). We also generated cultured human hepatocytes (HepG2) that lack RARβ (RARβ-KO) and treated them with ETOH. Here we show that the livers of BKO mice develop greater steatosis, oxidative stress (assessed by 4-HNE), cell proliferation, and hypertrophy on the ETOH diet when compared to wild type (WT). Compared to ETOH-WT mice, the ETOH-BKO mice also exhibit higher hepatic transcript levels of ATF4, MYC, a subset of integrated stress response (ISR) genes (Trib3, Asns, Nqo1, and Hmox1), and the common ATF4 and MYC target, 4EBP1(EIF4EBP1). In RARβ-KO HepG2 cells, ETOH treatments (24 and 72h) resulted in more rapid and greater development of reactive oxygen species compared to parental HepG2. Notably, even without ETOH, ATF4 protein was higher in the RARβ-KO than in parental HepG2. Conclusions: Our research identifies hepatocyte RARβ as a crucial negative regulator of oxidative stress, MYC, ATF4, and proliferation in ALD.

ORGANISM(S): Mus musculus

PROVIDER: GSE221713 | GEO | 2023/11/28

REPOSITORIES: GEO

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Project description:Drug-induced liver injury (DILI) is an important clinical problem. Here we used a genomics approach to establish the critical drug-induced toxicity pathways that act in synergy with the pro-inflammatory cytokine tumor necrosis factor (TNF) to cause cell death of liver HepG2 cells. Transcriptomics of the cell injury stress response pathways initiated by two hepatoxicants, diclofenac and carbamazepine, revealed the endoplasmic reticulum (ER) stress/translational initiation signaling and Nrf2 antioxidant signaling as two major affected pathways, which was similar to that observed for the majority of ~80 DILI compounds in primary human hepatocytes. The ER stress was primarily related to PERK and ATF4 activation and subsequent expression of CHOP, which was all independent of TNFÎ± signaling. Identical ATF4 dependent transcriptional programs were observed in primary human hepatocytes as well as primary precision cut human liver slices. Targeted RNA interference studies revealed that while ER stress signaling through IRE1Î± and ATF6 acted cytoprotective, activation of the ER stress protein kinase PERK and subsequent expression of CHOP was pivotal for the onset of drug/TNF-induced apoptosis. While inhibition of the Nrf2-dependent adaptive oxidative stress response enhanced the drug/TNF cytotoxicity, Nrf2 signaling did not affect CHOP expression. Both hepatotoxic drugs enhanced expression of the translational initiation factor EIF4A1, which was essential for CHOP expression and drug/TNF-mediated cell killing. Our data support a model in which enhanced drug-induced translation initiates PERK-mediated CHOP signaling in an EIF4A1 dependent manner, thereby sensitizing towards caspase-8-dependent TNF induced apoptosis. We sought to determine the effect of co-exposure of certain drugs associated with idiosyncratic DILI with the cytokine TNFalpha to mimic drug exposure with inflammation signaling in HepG2 cells Human hepatoma HepG2 cells were obtained from American Type Culture Collection (ATCC, Wesel, Germany), cultured in DMEM supplemented with 10% (v/v) FBS, 25 U/mL penicillin and 25 Âµg/mL streptomycin and used for experiments between passage 5 and 20.

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Retinoic Acid Receptor β Loss in Hepatocytes Increases Steatosis and Elevates the Integrated Stress Response in Alcohol-Associated Liver Disease

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