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LIX1L aggravates NASH-HCC progression by reprogramming of hepatic Metabolism and microenvironment via CD36

ABSTRACT: Limb expression 1-like protein (LIX1L) plays important role in various liver disorders, but its role and underlying mechanism in nonalcoholic hepatitis (NASH) and HCC progression remains obscure. Here, we report that LIX1L functions as a key integrative regulator linking lipid metabolism and inflammation, adipose tissue dysfunction and hepatic microenvironment reprogramming which promotes NASH progression. LIX1L significantly upregulated in NAFLD/NASH patients, mouse models and palmitic acid-stimulated hepatocytes. Lix1l deletion inhibits lipid deposition, inflammatory response and fibrosis in liver as well as adipocyte differentiation by downregulation of fatty acid translocase CD36 expression, alleviating NASH and associated HCC progression. In contrast, adeno-associated virus (AAV)-mediated LIX1L overexpression exacerbates NASH progression in mice. Mechanistically, metabolic stress promotes PARP1 mediated poly-ADP-ribosylation (PARylation) of LIX1L, subsequently increasing the stability and RNA binding ability of LIX1L protein. LIX1L binds to AU-rich element (ARE) in the 3’ untranslated region (UTR) of CD36 mRNA, thus attenuating CD36 mRNA decay. In NASH and associated HCC mouse models, LIX1L deficiency-mediated downregulation of CD36 suppresses adipogenesis, hepatic lipid uptake, and reprograms the tumor-prone liver microenvironment with increased cytotoxic T lymphocytes (CTLs), reduced immunosuppressive cell proportions. These data indicate a systematic function of LIX1L in the pathogenesis of NASH and underscore the PARP1/LIX1L/CD36 axis as a potential target for treatment of NASH and associated HCC.

ORGANISM(S): Mus musculus

PROVIDER: GSE264479 | GEO | 2024/04/25

REPOSITORIES: GEO

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Project description:Immunotherapy has opened hitherto unknown possibilities to treat cancer. Whereas some cancer types (e.g. melanoma) can be efficiently treated, others lack measurable positive effects (e.g. PDAC). Moreover, stratification of responders/non-responders is only possible in some cancer types (e.g. melanoma). Hepatocellular carcinoma (HCC) has a dismal prognosis, limited treatment options and survival benefit, and represents a potential cancer entity for successful immunotherapy. Here, we investigated NASH-triggered HCC in the context PD-1-targeted immunotherapy. Using flow cytometry, single cell RNA sequencing, immunohistochemistry and mass spectrometric analyses, we found a progressive increase of CD8+PD-1+ effector T-cells with a unique profile of exhaustion and activation markers rising with murine and human NASH severity. Notably, late-stage HCC treatment with PD-1-targeted immunotherapy enhanced hepatic carcinogenesis in mice. Dissecting potential mechanisms of action during tumor-initiation and -progression we analyzed the effects of PD-1-targeted immunotherapy at HCC initiation. PD-1-targeted immunotherapy induced a pro-tumorigenic environment, enhanced necro-inflammation and increased NAFLD-activation score (NAS), leading to increased liver cancer incidence, tumor number and nodule size. In contrast, anti-CD8 or anti-CD8/anti-NK1.1 treatment reduced NAS and abrogated the development of liver cancer, thus identifying CD8+PD-1+ T-cells as drivers of liver cancer in NASH-triggered HCC. Increased apoptotic signaling, STAT3 phosphorylation and hepatic proliferation were detected in intra-tumoral liver tissue upon PD-1-targeted immunotherapy. In line, PD-1-/- mice challenged with a NASH diet displayed early onset of hepatocarcinogenesis, corroborating the pro-tumorigenic role of absent or reduced PD-1. Mechanistically PD-1-targeted immunotherapy mainly affected hepatic abundance of CD8+PD-1+ T-cells, instead of altering the quality of Tox+CXCR6+ expressing CD8+PD-1+TNF+CD39+Gzmb+ T-cells found in NASH livers, leading to an aggressive, pro-tumorigenic liver environment. Single-cell mapping of human NASH-, borderline NASH- or unaffected livers corroborated our preclinical NASH results. Moreover, in human NASH livers a correlation of hepatic CD8+, PD-1+, TNF+ T-cells with fibrosis and NASH severity was observed. Accordingly, HCC patients with NASH etiology display a sharp increase in intra- and peri-tumoral CD8+ PD-1+ T-cells. In a cohort of 65 patients recruited across 6 centers in Germany and Austria, patients with NAFLD/NASH-driven HCC responded worse to PD-1-targeted immunotherapy by Nivolumab or Pembrolizumab compared to non-NAFLD patients. This resulted in significant reduced overall survival, in trends of faster disease progression and reduced progression free survival. Histological analysis of livers derived from HCC patients treated with PD-1-targeted immunotherapy displayed high levels of intra and peri-tumoral CD8+ PD-1+ T-cells and Ki67+ hepatocytes. Taken together, these data indicate that PD-1-targeted immunotherapy induces immune-related adverse effects in NAFLD/NASH-driven HCC through CD8+PD-1+ T-cells. Our data call for stratification of HCC patients subjected to PD-1-targeted immunotherapy, with NAFLD being a negative predictor.

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LIX1L aggravates NASH-HCC progression by reprogramming of hepatic Metabolism and microenvironment via CD36

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