Foxa1 Reduces Lipid Accumulation in Human Hepatocytes and Is Down-Regulated in Nonalcoholic Fatty Liver

Abstract

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 protein FATP2 and lowers fatty acid uptake. Foxa1 also increases the breakdown of fatty acids by inducing peroxisomal fatty acid β-oxidation 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 metabolic 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.

Interactions Between Nuclear Receptor SHP and FOXA1 Maintain Oscillatory Homocysteine Homeostasis in Mice

“…Interestingly, Moya et al reported that FOXA1 is involved in lipid metabolism in human liver. 31 Based on their gene expression database (GSE30450), overexpression of FOXA1 in primary human hepatocytes correlated with the induction of BHMT ( p = 0.05) and CTH ( p = 0.02) but the reduction of SHP (Fig. 3f), suggesting a direct regulation.…”

Genomics of human fatty liver disease reveal mechanistically linked lipid droplet–associated gene regulations in bland steatosis and nonalcoholic steatohepatitis

“…Moreover, FOXA1 and CLIC4 were frequently regulated amongst NAFLD patients and respond to mitochondrial stress with FOXA1 stimulating FA β-oxidation and ketone body synthesis 40 whereas CLIC4 regulations can be triggered by mitochondrial and ER stressinduced apoptosis 41 . Equally, NR5A2 (=liver receptor homolog1), i.e.…”

Hepatic Fatty Acid Trafficking: Multiple Forks in the Road

“…Additional work has also shown PPARg plays an important role in upregulating DNL especially in NAFLD (162)(163)(164). In contrast, FOXO1 and FOXA1 antagonize DNL (144,165,166).…”

“…In addition to its regulation by PPARa, hepatic FA uptake is also promoted by the liver X receptor (LXR) via changes in CD36 expression (143) and inhibited by FOXA1 via reduced FATP2 expression (144). There is also evidence that FOXA1, FOXA2, and hepatocyte nuclear factor-4a (HNF-4a) increase transcription of genes that promote hepatic FA oxidation and ketogenesis as a means to decrease hepatic TG content (144)(145)(146)(147)(148).…”