Analysis of hepatic genes involved in the metabolism of fatty acids and iron in nonalcoholic fatty liver disease

Abstract

Aims: Hepatic steatosis and iron cause oxidative stress, thereby progressing steatosis to steatohepatitis. We quantified the expression of genes involved in the metabolism of fatty acids and iron in patients with nonalcoholic fatty liver disease (NAFLD). Methods:The levels of transcripts for the following genes were quantified from biopsy specimens of 74 patients with NAFLD: thioredoxin (Trx), fatty acid transport protein 5 (FATP5), sterol regulatory element-binding protein 1c (SREBP1c), fatty acid synthase (FASN), acetyl-coenzyme A carboxylase (ACAC), peroxisome proliferative activated receptor a (PPARa), cytochrome P-450 2E1 (CYP2E1), acyl-coenzyme A dehydrogenase (ACADM), acyl-coenzyme A oxidase (ACOX), microsomal triglyceride transfer protein (MTP), transferrin receptor 1 (TfR1), transferrin receptor 2 (TfR2) and hepcidin. Twelve samples of human liver RNA were used as controls. Histological evaluation followed the methods of Brunt. Results:The levels of all genes were significantly higher in the NAFLD patients than in controls. The Trx level increased as the stage progressed. The levels of FATP5, SREBP1c, ACAC, PPARa, CYP2E1, ACADM and MTP significantly decreased as the stage and grade progressed (P < 0.05). Hepatic iron score (HIS) increased as the stage progressed. The TfR1 level significantly increased as the stage progressed (P < 0.05), whereas TfR2 level significantly decreased (P < 0.05). The ratio of hepcidin mRNA/ferritin (P < 0.001) or hepcidin mRNA/HIS (P < 0.01) was significantly lower in NASH patients than simple steatosis patients.Conclusions: Steatosis-related metabolism is attenuated as NAFLD progresses, whereas iron-related metabolism is exacerbated. Appropriate therapies should be considered on the basis of metabolic changes.

Blockade of B-cell-activating factor signaling enhances hepatic steatosis induced by a high-fat diet and improves insulin sensitivity

“…Although the contribution of de novo lipogenesis in the liver is very small, it has been reported that it is elevated in NAFLD, 27,28 and that the expression of ACC and FAS in the liver is increased in NAFLD patients, 29 as shown in the HFD-fed BAFF-R À / À mice in this study (Figure 4c). These data collectively indicate that the rate of fatty acid synthesis in the liver increases in HFD-fed BAFF-R À / À mice, despite the accumulation of fatty acids, and that the interaction between BAFF and BAFF-R interaction on hepatocytes may inhibit de novo lipogenesis in the liver.…”

Effects of insulin resistance and hepatic lipid accumulation on hepatic mRNA expression levels of apoB, MTP and L-FABP in non-alcoholic fatty liver disease

“…Since iron has a strong potential to produce oxidative stress, hepatic iron load is known to promote the progression of NASH (27,28). In the NAFLD liver, reduction in MTP expression levels and increased iron score were simultaneously observed during the progression of liver disease (29). Taken together, reduced MTP expression in NAFLD liver with IR or advanced steatosis may be induced by enhanced oxidative stress in these cellular circumstances.…”

Hyperinsulinemia induces hepatic iron overload by increasing liver TFR1 via the PI3K/IRP2 pathway

“…However, TFR1 was markedly increased in rats with chronic hyperinsulinemia without significant alteration in TFR2, indicating that long-lasting insulin infusion upregulated TFR1 in a sustainable way through a specific mechanism that was different from that for TFR2. It has been demonstrated in clinical studies that the liver TFR1 level is significantly upregulated (Mitsuyoshi et al 2009, Tsuchiya et al 2010 in patients with DIOS and even further increased as the stage of DIOS progressed, aggravating hepatic iron overload (Mitsuyoshi et al 2009). It was also reported in clinical studies that accumulation of hepatic iron might impair the insulin effect by reducing hepatic insulin Insulin increases intracellular iron content through TFR1 in HL-7702 cells.…”

“…Results from more recent studies demonstrated (Ruivard et al 2009, Tsuchiya et al 2010 have indicated that iron absorption was decreased in DIOS patients without altering the level of serum iron, indicating that the hepatic iron overload may be associated with cellular iron uptake, which is mainly determined by the level of TFRs. It was also reported that TFR1 level was elevated obviously in patients with DIOS (Mitsuyoshi et al 2009, Tsuchiya et al 2010) and this elevation was significantly and positively correlated with the hepatic iron content (Mitsuyoshi et al 2009). However, the effect of hyperinsulinemia on body iron stores and the level of liver TFRs remain elusive.…”