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.
Highlights
The term ‘‘nonalcoholic steatohepatitis’’ (NASH) was first used by Ludwig et al [1] in 1980 to describe the pathological and clinical features of nonalcoholic disease of the liver associated with pathological features most commonly seen in alcoholic liver disease itself
In parallel with the aldose reductase (AR) knockdown db/db mice, in C57BL/6 mice deficient in AR, we found that genetic ablation of AR gene significantly improved MCD diet inducedsteatohepatitis in non-obesity and non-diabetic mice (Fig. S1)
AR induction has been observed in some liver diseases conditions, including alcoholic liver disease, chronic hepatitis B and C, and hepatocellular carcinoma in humans and in hereditary hepatitis in rats [7,8,9]
Summary
The term ‘‘nonalcoholic steatohepatitis’’ (NASH) was first used by Ludwig et al [1] in 1980 to describe the pathological and clinical features of nonalcoholic disease of the liver associated with pathological features most commonly seen in alcoholic liver disease itself. Features of NASH on liver biopsy include steatosis, inflammation, liver cell injury, and varying degrees of fibrosis. It is a more advanced form of nonalcoholic fatty liver disease (NAFLD) and is becoming a major public health problem, but its underlying cause remains unclear. AR expression has been found to be induced in some tissues in some disease conditions other than diabetes. Brown et al reported that AR was induced in human livers obtained from patients undergoing liver transplantation for fulminant (acute) liver failure or for end-stage liver disease from cirrhosis due to various chronic liver diseases, including chronic hepatitis B and C, alcoholic liver disease, primary biliary cirrhosis, autoimmune hepatitis, and hepatocellular carcinoma [9]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
