Early Hepatic Transcriptomic Responses to High-Fat Diet in Apolipoprotein A-IV Knockout Mice

Background: Apolipoprotein A-IV (ApoA-IV) is involved in lipid metabolism and energy homeostasis, but its role in hepatic adaptation to dietary stress remains incompletely understood. This study aimed to determine whether ApoA-IV deficiency alters hepatic transcriptional responses to high-fat diet (HFD) and to examine how these molecular changes relate to biochemical and histological features of liver function. Methods: Male ApoA-IV knockout (KO) and wild-type (WT) mice were fed either a normal diet (ND) or HFD for 12 weeks. Liver tissues were subjected to whole-transcriptome RNA sequencing, followed by differential expression and functional enrichment analyses. Results: Histological examination revealed persistent lobular and portal inflammation accompanied by mild fibrosis in ApoA-IV-KO mice irrespective of diet, whereas steatosis and hepatocellular ballooning were absent in all groups. Both dietary intervention and genotype were associated with transcriptomic and biochemical alterations, although the identified changes were primarily evident at the level of specific genes and biological pathways. ApoA-IV deficiency was associated with a more limited set of diet-related transcriptomic changes, reflected by fewer differentially expressed genes and enriched functional categories compared to WT mice. Functional enrichment analyses identified alterations predominantly related to lipid and sterol metabolism, including the statin pathway, triglyceride metabolism, PPAR signaling and cytochrome P450-associated processes. Notably, the statin pathway was the only functional category consistently distinguishing ApoA-IV-deficient and WT mice regardless of diet. Additionally, HFD-fed ApoA-IV-KO mice exhibited elevated serum triglyceride, alanine aminotransferase and insulin levels, in contrast to WT mice. Conclusions: ApoA-IV deficiency was associated with the modulation of selected metabolic and inflammatory pathways involved in hepatic responses to dietary challenge. Cholesterol- and sterol-related pathways, including the statin pathway, represented the most consistent genotype-associated transcriptomic signature. Within the context of the present model, the findings suggest that ApoA-IV may contribute to hepatic responses during early stages of metabolic adaptation to dietary stress, although the biological significance of the observed transcriptomic differences requires further investigation.