Aldose Reductase Is Involved in the Development of Murine Diet-Induced Nonalcoholic Steatohepatitis

Abstract

Hepatic aldose reductase (AR) expression is known to be induced in liver diseases, including hepatitis and hepatocellular carcinoma. However, the role of AR in the development of these diseases remains unclear. We performed this current study to determine whether and how AR might be involved in the development of diet-induced nonalcoholic steatohepatitis. Our results showed that the level of AR protein expression was significantly higher in db/db mice fed the methionine-choline-deficient (MCD) diet than in mice fed the control diet. In parallel with the elevation in AR, steatohepatitis was observed in MCD diet-fed mice, and this diet-induced steatohepatitis was significantly attenuated by lentiviral-mediated knock-down of the AR gene. This suppressive effect of AR knock-down was associated with repressed levels of serum alanine aminotransferase and hepatic lipoperoxides, reduced mRNA and protein expression of hepatic cytochrome P450 2E1 (CYP2E1), and decreased mRNA expression of pro-inflammatory tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6). Moreover, AR-induced elevations on the level of CYP2E1 expression, reactive oxygen species, mRNA expression of TNF-α and IL-6 were confirmed in AML12 hepatocytes. Further, lentiviral-mediated knock-down of AR ameliorated MCD diet-induced collagen deposition in the livers of db/db mice. With the improvement in liver fibrosis, the mRNA levels of tissue inhibitor of metalloproteinase-1 (TIMP-1) and matrix metalloproteinase-2 (MMP-2), two genes involved in hepatic fibrogenesis, were found to be significantly suppressed, while TIMP-2 and MMP-13 were unaffected. Together these data indicate that inhibition of AR alleviates the MCD diet-induced liver inflammation and fibrosis in db/db mice, probably through dampening CYP2E1 mediated-oxidative stress and ameliorating the expression of pro-inflammatory cytokines.

Immunohistochemical determination of the extracellular matrix modulation in a rat model of choline‐deprived myocardium: the effects of carnitine

“…Moreover, MMP-2 has been shown to be upregulated in rat models of choline deficiency-mediated liver cirrhosis [54][55][56][57] and a similar pattern of expression has been observed for TIMP-1 (a) (b) Figure 1 Representative photos indicating the expression of the studied proteins (by brown staining) in the: (a) myocardium, interstitium and vessels; (b) interstitium and vessels (9200). [54,57,58], TIMP-2 [54] and MMP-9 [57]. On the contrary, the impact of inadequate levels of carnitine on MMPs modulation has been found to result in suppressed ECM degradation [59,60].…”

“…Unfortunately, most of these studies concerned mainly the liver since choline deficiency is a well‐established model of nonalcoholic fatty liver disease . Moreover, MMP‐2 has been shown to be upregulated in rat models of choline deficiency‐mediated liver cirrhosis and a similar pattern of expression has been observed for TIMP‐1 , TIMP‐2 and MMP‐9 . On the contrary, the impact of inadequate levels of carnitine on MMPs modulation has been found to result in suppressed ECM degradation .…”

“…Unfortunately, most of these studies concerned mainly the liver since choline deficiency is a well-established model of nonalcoholic fatty liver disease [53]. Moreover, MMP-2 has been shown to be upregulated in rat models of choline deficiency-mediated liver cirrhosis [54][55][56][57] and a similar pattern of expression has been observed for TIMP-1 (a) (b) Figure 1 Representative photos indicating the expression of the studied proteins (by brown staining) in the: (a) myocardium, interstitium and vessels; (b) interstitium and vessels (9200). [54,57,58], TIMP-2 [54] and MMP-9 [57].…”

Oxidized high-density lipoprotein accelerates atherosclerosis progression by inducing the imbalance between treg and teff in LDLR knockout mice

“…All blood examination including total cholesterol, triglycerides, HDL cholesterol, LDL cholesterol, fasting blood glucose (FBG), HbA1c, creatinine, and C‐reactive (CRP) was measured after an overnight fast of at least 12 h. Serum creatinine was measured by enzymatic method with commercial kits. HDL elution was separated using fast protein liquid chromatography and levels of TBARS in serum and HDL elution were detected with a commercial TBARS kit (Beyotime, China), which were quantified using malondialdehyde (MDA) as a standard .…”

Inhibition of aldose reductase ameliorates alcoholic liver disease by activating AMPK and modulating oxidative stress and inflammatory cytokines

“…The role of AR in the development of complications in diabetes is well-established (4). Additionally, hepatic AR expression has been observed to be induced in a number of liver disease conditions, including alcoholic liver disease, non-alcoholic fatty liver disease, hepatitis, cirrhosis and hepatocellular carcinoma (5)(6)(7)(8). It was previously reported that overexpression of AR induced the production of ROS and TNF-α in liver cells, and that administration of the AR inhibitor zopolrestat attenuated methionine-choline-deficient diet-induced hepatosteatosis and liver inflammation (8,9).…”