Association of TP53 with Defective Long Chain 3-Hydroxy acyl-CoA Dehydrogenase Induced Non-Cirrhotic Hepatocellular...

Background and Aims: Little is known about metabolic dysfunction-associated steatotic liver disease (MASLD) as a risk factor for hepatocellular carcinoma (HCC) in non-cirrhotic (HCC-NC) patients. In-house developed mouse models with defective lipid-metabolizing enzyme long-chain 3-hydroxy acyl-CoA dehydrogenase (LCHAD), coded by hydroxyacyl-CoA dehydrogenase trifunctional multienzyme complex subunit alpha (HADHA) gene, result in MASLD (steatosis) without cirrhosis leading to HCC-NC. The aims of the current investigations are to assess molecular markers and the associated molecular events that may lead to HCC-NC. Methods: cDNA array study of HCC patients was conducted to assess the expression of HADHA transcripts. Differentially expressed proteins identified between wild-type (WT) and heterozygous mice with no cancer (HT) from a previous study were subjected to Ingenuity Pathway Analysis (IPA). Western blotting was performed to assess the expression of proteins. Results: IPA of the differentially expressed proteins between WT and HT mice results in two biological networks (network 1 and network 2), which pointed to an important role of p53 in HCC-NC. Validation of the levels of MDM2 and p53 also highlights the role of MDM2-p53 axis in HCC-NC. All the focus molecules in network 1 and network 2 are either presented as tumor suppressor/promoter of carcinogenesis or serum markers for early HCC diagnosis. The hepatotoxicity report from IPA further identified four functional groups including liver steatosis, glutathione depletion, hepatocellular carcinoma, and liver hyperplasia/hyperproliferation. Conclusions: This study suggests that impaired fatty oxidation may play a role in the development of HCC associated with steatosis but without cirrhosis (HCC-NC). Defective LCHAD is a novel etiology for HCC.