5-Aminoimidazole-4-carboxamide-1-β-D-ribofuranoside Attenuates High Fat, High Fructose Diet-induced Fatty Liver and Fibrosis in Mice.

Abstract

The liver is a vital organ in the human body and is the primary site for lipid metabolism. Impaired lipid metabolism causes an accumulation of lipids in the liver, a discernible indication of non-alcoholic fatty liver disease (NAFLD). The condition is characterized by pathological alterations in the liver like steatosis, fibrosis and cirrhosis. 5′ Adenosine monophosphate-activated protein kinase (AMPK) maintains energy balance by regulating glucose and lipid metabolism. Dysregulation of AMPK is observed in NAFLD. The present work investigates the effect of an AMPK activator, 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR), on lipid levels, peroxisome proliferator-activated receptor (PPAR)-α, a nuclear receptor and cytoskeletal proteins α – smooth muscle actin (α-SMA) and cytokeratin 18 (CK18) and bilirubin levels in C57BL/6 mice fed high fat, high fructose diet (HFFD). The animals were divided into four groups (n=6, each group), and the feeding duration was ten weeks. The standard pellet was provided to groups 1 and 4 animals while HFFD was fed to animals of two groups (Groups 2 and 3) to induce fatty liver. AICAR injection (150 mg/kg bw/day, i.p.) was given to groups 3 and 4 animals on the 9th and 10th weeks. An equal volume of saline was injected into groups 1 and 2 animals. HFFD-fed mice showed increased levels of cholesterol, free fatty acids (FFAs) and CK18 with decreased bilirubin levels in plasma along with downregulated PPAR- α mRNA level and upregulated expression of α-SMA mRNA in the liver. Mice given HFFD and AICAR had significantly reduced cholesterol and FFA levels, increased bilirubin levels and reduced CK18 protein in plasma. The hepatic mRNA expression of PPAR-α was upregulated, while AICAR downregulated α-SMA expression. These findings suggest that AICAR regulates lipid metabolism, fibrogenesis and overall liver integrity. Thus, AICAR serves as a potential therapeutic measure for diet-induced fatty liver and the accompanying changes in the liver.