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Human hepatoma Huh-7 cell culture models deficient in apolipoprotein B secretion

ABSTRACT: High plasma apolipoprotein B (apoB)-containing lipoproteins are both a biomarker and causal mediator of many metabolic diseases. Inhibition of apoB and MTP decreases plasma lipid levels but at a risk of lipid accumulation in tissues. Whole body knock out of MTP and APOB are embronically lethal. Therefore, we created a human hepatome cells line (Ako) deficient in APOB gene to understand the global consequences of APOB loss. APOB gene deletion significantly reduced apoB mRNA and protein levels in the Ako cells compared to control cells. These cells supported apoB48 secretion when transfected with apoB48 expression plasmids. These cells did not accumulate significant amounts of triglyceride. KEGG pathway analysis of RNA-Seq data showed a significant increase in DNA replication/repair pathway and complement/coagulation cascade in the Ako cells. The most downregulated pathways included the PI3k-Akt signaling and MAPK signaling pathways. Total proteome analysis of secretory proteins identifed Vitamin D binding protein as the most upregulated protein while apoB was the most dowregulated protein in these cells. Since both APOB and MTP are important part of the lipoprotein assmebly and secretion, we also perfrmed total transcriptome analysis for the MTP deficient Huh-7 (Mko-3) cells. We found differential expression of some the pathways in both Ako and Mko-3 cells such as DNA replication, base excision repair, steroid hormone biosynthesis and pathways reated to breast cancer. These cells may be useful in studying structure-function analysis of apoB peptides and to address the cellular consequences of disruptions in lipoprotein assembly and secretion. However; further detailed studies are needed to establish how apoB regulates these pathways

ORGANISM(S): Homo sapiens

PROVIDER: GSE269949 | GEO | 2025/07/23

REPOSITORIES: GEO

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Project description:Triglyceride accumulation in nonalcoholic fatty liver (NAFL) results from unbalanced lipid metabolism which, in the liver, is controlled by several transcription factors. The Foxa subfamily of winged helix/forkhead box (Fox) transcription factors comprises three members which play important roles in controlling both metabolism and homeostasis through the regulation of multiple target genes in the liver, pancreas and adipose tissue. In the mouse liver, Foxa2 is repressed by insulin and mediates fasting responses. Unlike Foxa2, however, the role of Foxa1 in the liver has not yet been investigated in detail. In this study, we evaluate the role of Foxa1 in two human liver cell models, primary cultured hepatocytes and HepG2 cells, by adenoviral infection. Moreover, human and rat livers were analyzed to determine Foxa1 regulation in NAFL. Results demonstrate that Foxa1 is a potent inhibitor of hepatic triglyceride synthesis, accumulation and secretion by repressing the expression of multiple target genes of these pathways (e.g., GPAM, DGAT2, MTP, APOB). Moreover, Foxa1 represses the fatty acid transporter FATP2 and lowers fatty acid uptake. Foxa1 also increases the breakdown of fatty acids by inducing HMGCS2 and ketone body synthesis. Finally, Foxa1 is able to largely up-regulate UCP1, thereby dissipating energy and consistently decreasing the mitochondria membrane potential. We also report that human and rat NAFL have a reduced Foxa1 expression, possibly through a protein kinase C-dependent pathway. We conclude that Foxa1 is an antisteatotic factor that coordinately tunes several lipid metabolism pathways to block triglyceride accumulation in hepatocytes. However, Foxa1 is down-regulated in human and rat NAFL and, therefore, increasing Foxa1 levels could protect from steatosis. Altogether, we suggest that Foxa1 could be a novel therapeutic target for NAFL disease and insulin resistance. To determine the global impact of Foxa1 on human liver gene transcription, microarray expression analyses were performed in HepG2 cells transfected with Ad-Foxa1 or Ad-Control. We used microarrays to detail the global programme of gene expression in HepG2 cells infected with Ad-Foxa1 or control adenovirus (insertless Ad-pACC).

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Human hepatoma Huh-7 cell culture models deficient in apolipoprotein B secretion

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