
-   ApoA4 is known to exert anti-inflammatory effects as part of the inflammatory response. ApoA4 stimulates the gene expression of SERPINA3 in mouse hepatocytes both in vivo and in vitro, and the transcriptional response of SERPINA3 to ApoA4 is regulated through the binding of ApoA4 with nuclear receptors NR4A1 and NR1D1 on the SERPINA3 promoter [PMID: 28412351].
-   In mice hepatocytes, apoA-IV inhibits hepatic gluconeogenesis by decreasing Glc-6-Pase and PEPCK gene expression through NR1D1 [PMID: 24311788].
-   The ApoA-IV-induced increase in NR4A1 expression in hepatocytes mediates further repression of gluconeogenesis [PMID: 26556724].
-   Bacterial endotoxin lipopolysaccharide (LPS) challenge can activate a stress-inducible, liver-enriched transcription factor, CREBH, in mouse liver tissues in a toll-like receptor (TLR)/MyD88-dependent manner. CREBH can directly activate the expression of the gene encoding Apolipoprotein A4 (ApoA4) under LPS challenge, leading to modulation of high-density lipoprotein (HDL) in animals. The CREBH modulation of lipid profiles may protect the liver from injuries upon the LPS exposure [PMID: 27637329].
-   Human leucine zipper protein (LZIP) regulates the expression of genes involved in inflammation, cell migration, stress response, and LZIP and APOA4 were found to be highly expressed in human steatosis samples. Under Golgi stress conditions, LZIP undergoes proteolytic cleavage and is phosphorylated by AKT to protect against proteasome degradation. The stabilized N-terminal LZIP translocates to the nucleus, where it directly binds to the APOA4 promoter, leading to APOA4 induction. LZIP-induced APOA4 expression results in increased absorption of surrounding free fatty acids [PMID: 28246167].
-   *ApoA4* deficiency is known to increase the hepatic lipid burden, insulin resistance, and metabolic inflammation. Gene expression was assessed by scRNA-seq on liver immune cells from wild type and *ApoA4*\-deficient mice administered a high-fat diet. *ApoA4* deficiency resulted in higher *Lgals3*, *Ctss*, *Fcgr2b*, *Spp1*, *Cxcl2*, and *Elane* levels and lower *Nr4a1* levels in hepatic immune cells. These genes were consistent with human nonalcoholic fatty liver disease (NAFLD)-associated marker genes linked to disease severity. The expression of NE and IL-1beta in granulocytes and macrophages were key ApoA4 targets, suggesting that NE and IL-1beta play a vital role in the aggravation of NAFLD [PMID: 36426356].

## Summary

In liver diseases and toxicities, ApoA4 is upregulated as a response to disturbances in lipid metabolism and inflammatory stress [CS: 7]. Specifically, in conditions like hepatic steatosis where there's excess fat in the liver, ApoA4 helps by activating key enzymes like lipoprotein lipase [CS: 6] and lecithin-cholesterol acyltransferase [CS: 6], aiding in lipid breakdown and HDL formation [CS: 7]. This suggests its role in managing the lipid overload [CS: 8].

Moreover, in liver toxicity scenarios, such as with Bisphenol S exposure, ApoA4's increase is linked to its function in lipid metabolism, counteracting the buildup of hepatic triglycerides [CS: 5]. In inflammatory responses, like those triggered by bacterial endotoxins, ApoA4 interacts with nuclear receptors NR4A1 [CS: 6] and NR1D1 [CS: 6], influencing inflammatory gene expression [CS: 7]. This interaction indicates its role in moderating inflammation, aiming to protect the liver from further damage [CS: 8].
