Dataset Information

Dietary and Genetic Cholesterol Loading Rather Than Steatosis Promotes Liver Tumorigenesis and NASH-Driven HCC.

ABSTRACT: The association of nonalcoholic steatohepatitis (NASH) with obesity and type 2 diabetes is a major determinant factor for the continued rise of NASH-driven HCC. Unfortunately, the mechanisms underlying the progression from NASH to HCC are not well-understood. Steatosis is characterized by the accumulation of different lipid species, and cholesterol has emerged as an important player in NASH development, which has been shown to promote NASH-driven HCC. However, recent findings indicated a tumor suppressor role of cholesterol in liver carcinogenesis and HCC development. Thus, we examined the contribution of hepatic steatosis with or without cholesterol accumulation induced by dietary or genetic approaches in liver tumorigenesis and whether the role of cholesterol in NASH-driven HCC is species-dependent. While diethylnitrosamine (DEN) treatment to rats or mice fed a choline-deficient diet decreased the hepatic steatosis, feeding an atherogenic diet enriched in cholesterol potentiated the liver tumor markers. Similar effects were observed in DEN-treated transgenic SREBP-2 mice but not wild-type (WT) mice fed a regular chow diet. Remarkably, long-term feeding of a high-fat high-cholesterol diet (HFHC) but not a high-fat diet (HFD) to WT mice caused severe NASH with spontaneous progression to HCC. A similar outcome was observed in MUP-uPA transgenic mice fed a HFHC diet, which resulted in increased liver tumors and expression of the genes involved in the immune checkpoints. Ezetimibe treatment ameliorated chronic liver disease and, more importantly, tumor multiplicity in HFHC-fed MUP-uPA mice or DEN-treated WT mice. Thus, these results revealed a differential role of steatosis and cholesterol in NASH-driven HCC and indicated that the tumor-promoter role of cholesterol is species-independent and associated with impaired immunosurveillance.

SUBMITTER: Ribas V

PROVIDER: S-EPMC8393403 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:Obesity is a significant global health concern. Non-alcoholic fatty liver disease and non-alcoholic steatohepatitis (NASH) are common risk factors for hepatocellular carcinoma (HCC) and are closely associated with metabolic comorbidities, including obesity and diabetes. The TP53 tumor suppressor is the most frequently mutated gene in liver cancers, with half of these alterations being missense mutations. These mutations produce highly abundant proteins in cancer cells which have both inhibitory effects on wildtype (WT) p53, and gain-of-function (GOF) activities that contribute to tumor progression. A Western diet increases p53 activity in the liver. To elucidate the functional consequences of Trp53 mutations in a NASH-driven liver tumorigenesis model, we generated somatic mouse models with Trp53 deletion or the missense hotspot mutant p53R245W only in hepatocytes and placed mice on a high-fat, choline-deficient diet. p53R245W in the presence of diet increased fatty liver, compensatory proliferation in the liver parenchyma, and enriched genes of tumor-promoting pathways such as KRAS signaling, MYC, and epithelial-mesenchymal transition when compared with controls in the premalignant liver. Moreover, p53R245W suppressed transcriptional activity of WT p53 in the liver in vivo under metabolic challenges, and shortened survival and doubling of HCC incidence as compared with control heterozygous mice. Complete loss of Trp53 also significantly accelerated liver tumor incidence and lowered time-to-tumor development compared with WT controls. p53R245W GOF properties increased carcinoma initiation, fueled mixed hepatocholangial carcinoma incidence, and tripled metastatic disease. Collectively, our in vivo studies indicate that p53R245W has stronger tumor promoting activities than Trp53 loss in the context of NASH.SignificanceUsing somatic NASH-driven mouse models with p53 deletion or mutant p53R245W only in hepatocytes, we discovered that p53R245W increased carcinoma initiation, fueled hepatocholangial carcinoma incidence, and tripled metastases.

Project description:ObjectiveObesity-related chronic inflammation plays an important role in the development of Metabolic Associated Fatty Liver Disease (MAFLD). Although the contribution of the pro-inflammatory NF-κB signaling pathway to the progression from simple steatosis to non-alcoholic steatohepatitis (NASH) is well-established, its role as an initiator of hepatic steatosis and the underlying mechanism remains unclear. Here, we investigated the hypothesis that the hepatocytic NF-κB signaling pathway acts as a metabolic regulator, thereby promoting hepatic steatosis development.MethodsA murine model expressing a constitutively active form of IKKβ in hepatocytes (Hep-IKKβca) was used to activate hepatocyte NF-κB. In addition, IKKβca was also expressed in hepatocyte A20-deficient mice (IKKβca;A20LKO). A20 is an NF-κB-target gene that inhibits the activation of the NF-κB signaling pathway upstream of IKKβ. These mouse models were fed a sucrose-rich diet for 8 weeks. Hepatic lipid levels were measured and using [1-13C]-acetate de novo lipogenesis and cholesterol synthesis rate were determined. Gene expression analyses and immunoblotting were used to study the lipogenesis and cholesterol synthesis pathways.ResultsHepatocytic NF-κB activation by expressing IKKβca in hepatocytes resulted in hepatic steatosis without inflammation. Ablation of hepatocyte A20 in Hep-IKKβca mice (IKKβca;A20LKO mice) exacerbated hepatic steatosis, characterized by macrovesicular accumulation of triglycerides and cholesterol, and increased plasma cholesterol levels. Both De novo lipogenesis (DNL) and cholesterol synthesis were found elevated in IKKβca;A20LKO mice. Phosphorylation of AMP-activated kinase (AMPK) - a suppressor in lipogenesis and cholesterol synthesis - was decreased in IKKβca;A20LKO mice. This was paralleled by elevated protein levels of hydroxymethylglutaryl-CoA synthase 1 (HMGCS1) and reduced phosphorylation of HMG-CoA reductase (HMGCR) both key enzymes in the cholesterol synthesis pathway. Whereas inflammation was not observed in young IKKβca;A20LKO mice sustained hepatic NF-κB activation resulted in liver inflammation, together with elevated hepatic and plasma cholesterol levels in middle-aged mice.ConclusionsThe hepatocytic IKK:NF-κB axis is a metabolic regulator by controlling DNL and cholesterol synthesis, independent of its central role in inflammation. The IKK:NF-κB axis controls the phosphorylation levels of AMPK and HMGCR and the protein levels of HMGCS1. Chronic IKK-mediated NF-κB activation may contribute to the initiation of hepatic steatosis and cardiovascular disease risk in MAFLD patients.

Dataset Information

Dietary and Genetic Cholesterol Loading Rather Than Steatosis Promotes Liver Tumorigenesis and NASH-Driven HCC.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets