Alleviation of high-fat diet-induced fatty liver damage in group IVA phospholipase A2-knockout mice

Abstract

Hepatic fat deposition with hepatocellular damage, a feature of non-alcoholic fatty liver disease, is mediated by several putative factors including prostaglandins. In the present study, we examined whether group IVA phospholipase A(2) (IVA-PLA(2)), which catalyzes the first step in prostanoid biosynthesis, is involved in the development of fatty liver, using IVA-PLA(2)-knockout mice. Male wild-type mice on high-fat diets (20% fat and 1.25% cholesterol) developed hepatocellular vacuolation and liver hypertrophy with an increase in the serum levels of liver damage marker aminotransferases when compared with wild-type mice fed normal diets. These high-fat diet-induced alterations were markedly decreased in IVA-PLA(2)-knockout mice. Hepatic triacylglycerol content was lower in IVA-PLA(2)-knockout mice than in wild-type mice under normal dietary conditions. Although high-fat diets increased hepatic triacylglycerol content in both genotypes, the degree was lower in IVA-PLA(2)-knockout mice than in wild-type mice. Under the high-fat dietary conditions, IVA-PLA(2)-knockout mice had lower epididymal fat pad weight and smaller adipocytes than wild-type mice. The serum level of prostaglandin E(2), which has a fat storage effect, was lower in IVA-PLA(2)-knockout mice than in wild-type mice, irrespective of the kind of diet. In both genotypes, high-fat diets increased serum leptin levels equally between the two groups, but did not affect the serum levels of adiponectin, resistin, free fatty acid, triacylglycerol, glucose, or insulin. Our findings suggest that a deficiency of IVA-PLA(2) alleviates fatty liver damage caused by high-fat diets, probably because of the lower generation of IVA-PLA(2) metabolites, such as prostaglandin E(2). IVA-PLA(2) could be a promising therapeutic target for obesity-related diseases including non-alcoholic fatty liver disease.

Figure 1. Microscopic views of the liver in wild-type and IVA-PLA₂-knockout mice.

Wild-type and IVA-PLA₂-knockout (KO) mice were fed normal (N) or high-fat (HF) diets for 8 (A) or 16 (B) weeks and fasted. Representative liver sections stained with hematoxylin-eosin are shown. IVA-PLA₂ deficiency suppressed the hepatic fat deposition under the HF feeding. CV, central vein; PV, portal vein. Original magnification, ×4 and ×20.

Figure 2. Hepatic triacylglycerol content in wild-type and IVA-PLA₂-knockout mice.

Wild-type and IVA-PLA₂-knockout mice were fed normal (N) or high-fat (HF) diets for 8 weeks and fasted. Triacylglycerol content in the liver was measured (n = 5–7). IVA-PLA₂ deficiency suppressed the accumulation of hepatic triacylglycerol under the HF feeding. *P<0.005 versus wild-type mice fed normal diets, **P<0.05 versus wild-type mice fed normal diets, ***P<0.01 versus wild-type mice fed HF diets.

Figure 3. Macroscopic views of the liver in wild-type and IVA-PLA₂-knockout mice.

Wild-type (WT) and IVA-PLA₂-knockout (KO) mice were fed normal (N) or high-fat (HF) diets for 16 weeks and fasted. Representative photographs of the liver in each mouse are shown. IVA-PLA₂ deficiency suppressed the hepatic hypertrophy induced by HF feeding.

Figure 4. Microscopic views of epididymal fat pads in wild-type and IVA-PLA₂-knockout mice.

Wild-type and IVA-PLA₂-knockout (KO) mice were fed normal or high-fat (HF) diets for 8 weeks and fasted. Representative epididymal fat pad sections stained with hematoxylin-eosin are shown. Original magnification, ×4. IVA-PLA₂ deficiency suppressed the expansion of epididymal adipocytes induced by HF feeding.

Figure 5. Lipoprotein profiles under HF dietary conditions.

Wild-type (WT) and IVA-PLA₂-knockout (KO) mice were fed normal or HF diets for 16 weeks and fasted. The serum levels of VLDL, LDL, and HDL were analyzed. Each trace represents the mean (n = 4–6). IVA-PLA₂ deficiency reduced the increased serum level of LDL by HF feeding.

Figure 6. Serum levels of adipokines in wild-type and IVA-PLA₂-knockout mice.

Wild-type and IVA-PLA₂-knockout (KO) mice were fed normal (N) or high-fat (HF) diets for 8 weeks and fasted. The serum levels of adiponectin (A), leptin (B), and resistin (C) were measured (n = 4–6). *P<0.05 versus wild-type mice fed normal diets, **P<0.05 versus IVA-PLA₂-knockout mice fed normal diets. No significant differences in the serum levels of adipokines were detected between the two genotypes.