Dietary Inulin Alleviates Hepatic Steatosis and Xenobiotics-Induced Liver Injury in Rats Fed a High-Fat and High-Sucrose Diet: Association with the Suppression of Hepatic Cytochrome P450 and Hepatocyte Nuclear Factor 4α Expression

Abstract

ABSTRACT:Inulin enzymatically synthesized from sucrose is a dietary component that completely escapes glucide digestion. Supplementing inulin to a high-fat and high-sucrose diet (HF) ameliorated hypertriglycemia and hepatic steatosis in 8-week-fed rats by suppressing elevated levels of serum triacylglycerols, fatty acids, and glucose, and the accumulation of hepatic triacylglycerols and fatty acids. Inulin intake prevented phenobarbital (PB)-and dexamethasone-induced liver injuries in the HF group. No significant alteration in the baseline expression of CYP2B, CYP2C11, CYP3A, and NADPH-cytochrome P450 (P450) reductase mRNAs and proteins was found. In contrast, baseline and PB-treated expressions of CYP2E1 mRNA were reduced in HF-fed rats. The induction of P450s in response to PB was affected by the nutritional status of the rats; mRNA levels of CYP2B1 and CYP3A1 after PB treatment, as assessed by quantitative real-time polymerase chain reaction analysis were reduced in the inulin-supplemented HF (HF؉I) group, compared with those in the HF group. Western blot analysis detected the corresponding changes of CYP2B and CYP3A proteins. These alterations were correlated with changes in hepatic thiobarbituric acid-reactive substances. Furthermore, no significant difference in the expression of nuclear receptors constitutive androstane receptor, pregnane X receptor, and retinoid X receptor ␣ and coactivator peroxisome proliferator-activated receptor-␥ coactivator 1␣ proteins was found in the hepatic nucleus between the HF and HF؉I groups, but the expression of hepatocyte nuclear factor ␣ (HNF4␣) protein was significantly reduced in the HF؉I group. Taken together, these results indicate that inulin intake ameliorates PB-induced liver injury, associated with a decline in lipid accumulation and PB-induced expression of CYP2B and CYP3A, which may be related by a reduction in the nuclear expression of HNF4␣.

Nutritional Status Affects Fluvastatin-Induced Hepatotoxicity and Myopathy in Rats

“…Nutritional status such as starvation, fasting, and a high-lipid diet and pathophysiological factors such as diabetes have been reported to affect liver drug-metabolizing phase I enzymes, leading to the altered hepatic metabolism of drugs, carcinogens, steroid hormones, and fatty acids (Ding et al, 2006;Sugatani et al, 2006;Osabe et al, 2008). The accumulation in the liver of triacylglycerols, defined as hepatic steatosis, is proposed to be the first stage of more severe liver diseases such as nonalcoholic steatohepatitis, which shows histological signs of fibrosis and necroinflammation, through cirrhosis, terminal liver failure, and hepatocellular carcinoma (Bugianesi et al, 2002).…”

Protective effects of the herbal medicine goshajinkigan in a rat model of non-alcoholic fatty liver disease

“…Furthermore, administration of GJ to rats with streptozotocin (STZ)-induced diabetes reduced hyperinsulinemia; GJ mediated its effects via the NO pathway (7). Further, the homeostasis model assessment-insulin resistance (HOMA-R) index in patients with type 2 diabetes significantly decreased after GJ treatment (8). Moreover, we observed that STZ-induced diabetic rats which were fed chow containing 1% GJ exhibited more stable levels of serum triglyceride, cholesterol, and free fatty acid (unpublished).…”

“…Accumulation of triacylglycerols, termed as hepatic steatosis, is proposed to be an indication of more severe liver diseases including non-alcoholic steatohepatitis, which is characterized by fibrosis and necroinflammation and can progress to cirrhosis and terminal liver failure (1). Sugatani et al found that intake of a high-fat and high-sucrose diet for 8 weeks resulted in marked accumulation of hepatic and serum triacylglycerols in rats, leading to hepatic steatosis but not hepatic necroinflammatory lesions (8). Goshajinkigan (GJ), an herbal medicine, has been widely used to treat patients with melosalgia, pain in the lower back, and numbness (7,11).…”

“…Increased hepatic production and accumulation of triacylglycerols are directly related to metabolic syndromes (8). Accumulation of triacylglycerols, termed as hepatic steatosis, is proposed to be an indication of more severe liver diseases including non-alcoholic steatohepatitis, which is characterized by fibrosis and necroinflammation and can progress to cirrhosis and terminal liver failure (1).…”

“…The rats were maintained on a standard powder diet (MF ® diet; Oriental Yeast, Tokyo, Japan) for 1 week. They had free access to rat chow and water, and were kept in a room maintained at 22°C ± 2°C with a 12-h light/dark cycle (diurnal time, 8 ); and 1 g each of Cinnamomi Cortex (Cinnamomum cassia Blume) and Aconiti Tuber (Aconitum carmichaelii Debeaux). The rats were randomly divided into 4 groups with 8 rats per group.…”