Treatment with ginger ameliorates fructose-induced Fatty liver and hypertriglyceridemia in rats: modulation of the hepatic carbohydrate response element-binding protein-mediated pathway

Abstract

Ginger has been demonstrated to improve lipid derangements. However, its underlying triglyceride-lowering mechanisms remain unclear. Fructose overconsumption is associated with increase in hepatic de novo lipogenesis, thereby resulting in lipid derangements. Here we found that coadministration of the alcoholic extract of ginger (50 mg/kg/day, oral gavage, once daily) over 5 weeks reversed liquid fructose-induced increase in plasma triglyceride and glucose concentrations and hepatic triglyceride content in rats. Plasma nonesterified fatty acid concentration was also decreased. Attenuation of the increased vacuolization and Oil Red O staining area was evident on histological examination of liver in ginger-treated rats. However, ginger treatment did not affect chow intake and body weight. Further, ginger treatment suppressed fructose-stimulated overexpression of carbohydrate response element-binding protein (ChREBP) at the mRNA and protein levels in the liver. Consequently, hepatic expression of the ChREBP-targeted lipogenic genes responsible for fatty acid biosynthesis was also downregulated. In contrast, expression of neither peroxisome proliferator-activated receptor- (PPAR-) alpha and its downstream genes, nor PPAR-gamma and sterol regulatory element-binding protein 1c was altered. Thus the present findings suggest that in rats, amelioration of fructose-induced fatty liver and hypertriglyceridemia by ginger treatment involves modulation of the hepatic ChREBP-mediated pathway.

Figure 1

Intakes of fructose (a) and laboratory chow (b), and body weight (c) in water-control, 10% fructose solution-control, and fructose pair-fed ginger-treated rats. Animals were coadministered with ginger extract (20 or 50 mg/kg/day) or vehicle (ginger: 0 mg/kg, 5% Gum Arabic) by oral gavage daily for 5 weeks. Data are means ± SEM (n = 6 each group). *P < 0.05.

Figure 2

Plasma total cholesterol (a), triglyceride (b), NEFA (c), glucose (d), and insulin (e) concentrations in water-control, 10% fructose solution-control, and fructose pair-fed ginger-treated rats at week 5. Animals were coadministered with ginger extract (20 or 50 mg/kg/day) or vehicle (ginger: 0 mg/kg, 5% Gum Arabic) by oral gavage daily for 5 weeks. Data are means ± SEM (n = 6 each group). *P < 0.05.

Figure 3

Liver weight (a), the ratio of liver weight to body weight (b), hepatic triglyceride content (c), and Oil Red O staining area (d) in water-control, 10% fructose solution-control, and fructose pair-fed ginger-treated rats at week 5. Animals were coadministered with ginger extract (20 or 50 mg/kg/day) or vehicle (ginger: 0 mg/kg, 5% Gum Arabic) by oral gavage daily for 5 weeks. Data are means ± SEM (n = 6 each group). *P < 0.05.

Figure 4

Representative images showing histology of liver (hematoxylin and eosin-staining, (a)–(c); Oil Red O staining, (d)–(f). X200) in water-control, 10% fructose solution-control, and fructose pair-fed ginger-treated rats at week 5. Animals were coadministered with ginger extract (50 mg/kg/day) or vehicle (ginger: 0 mg/kg, 5% Gum Arabic) by oral gavage daily for 5 weeks. Data are means ± SEM (n = 6 each group). *P < 0.05.

Figure 5

Hepatic mRNA expression of PPAR-γ (a), sterol regulatory element-binding protein (SREBP)1c (b), carbohydrate response element-binding protein (ChREBP) (c), and nuclear ChREBP protein expression (d) in water-control, 10% fructose solution-control, and fructose pair-fed ginger-treated rats at week 5. Animals were coadministered with ginger extract (50 mg/kg/day) or vehicle (ginger: 0 mg/kg, 5% Gum Arabic) by oral gavage daily for 5 weeks. mRNA was determined by real-time PCR. Protein expression was determined by western blot. Data are means ± SEM (n = 6 each group). *P < 0.05.

Figure 6

Hepatic mRNA expression of acetyl-CoA carboxylase (ACC)1 (a), fatty acid synthase (FAS) (b), stearoyl-CoA desaturase (SCD)1 (c), and glucose-6-phosphatase (G6Pase) (d) in water-control, 10% fructose solution-control, and fructose pair-fed ginger-treated rats at week 5. Animals were coadministered with ginger extract (50 mg/kg/day) or vehicle (ginger: 0 mg/kg, 5% Gum Arabic) by oral gavage daily for 5 weeks. mRNA was determined by real-time PCR. Data are means ± SEM (n = 6 each group). *P < 0.05.

Figure 7

Hepatic mRNA expression of peroxisome proliferator-activated receptor-(PPAR-) α (a), carnitine palmitoyltransferase (CPT)1a (b), acyl-CoA oxidase (ACO) (c), and CD36 (d) in water-control, 10% fructose solution-control, and fructose pair-fed ginger-treated rats at week 5. Animals were coadministered with ginger extract (50 mg/kg/day) or vehicle (ginger: 0 mg/kg, 5% Gum Arabic) by oral gavage daily for 5 weeks. mRNA was determined by real-time PCR. Data are means ± SEM (n = 6 each group). *P < 0.05.