Menhaden Oil Decreases High-Fat Diet-Induced Markers of Hepatic Damage, Steatosis, Inflammation, and Fibrosis in Obese Ldlr(-/-) Mice
ABSTRACT The frequency of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) has increased in parallel with obesity in the United States. NASH is progressive and characterized by hepatic damage, inflammation, fibrosis, and oxidative stress. Because C20-22 (n-3) PUFA are established regulators of lipid metabolism and inflammation, we tested the hypothesis that C20-22 (n-3) PUFA in menhaden oil (MO) prevent high-fat (HF) diet-induced fatty liver disease in mice. Wild-type (WT) and Ldlr(-/-) C57BL/6J mice were fed the following diets for 12 wk: nonpurified (NP), HF with lard (60% of energy from fat), HF-high-cholesterol with olive oil (HFHC-OO; 54.4% of energy from fat, 0.5% cholesterol), or HFHC-OO supplemented with MO (HFHC-MO). When compared with the NP diet, the HF and HFHC-OO diets induced hepatosteatosis and hepatic damage [elevated plasma alanine aminotransferase (ALT) and aspartate aminotransferases] and elevated hepatic expression of markers of inflammation (monocyte chemoattractant protein-1), fibrosis (procollagen 1α1), and oxidative stress (heme oxygenase-1) (P ≤ 0.05). Hepatic damage (i.e., ALT) correlated (r = 0.74, P < 0.05) with quantitatively higher (>140%, P < 0.05) hepatic cholesterol in Ldlr(-/-) mice fed the HFHC-OO diet than WT mice fed the HF or HFHC-OO diets. Plasma and hepatic markers of liver damage, steatosis, inflammation, and fibrosis, but not oxidative stress, were lower in WT and Ldlr(-/-) mice fed the HFHC-MO diet compared with the HFHC-OO diet (P < 0.05). In conclusion, MO [C20-22 (n-3) PUFA at 2% of energy] decreases many, but not all, HF diet-induced markers of fatty liver disease in mice.
- SourceAvailable from: Si-Yuan Pan[Show abstract] [Hide abstract]
ABSTRACT: Hyperlipidemia is referred to as hypercholesterolemia, hypertriglyceridemia, or both in combined hyperlipidemia. Here, a novel mouse model of combined hyperlipidemia is described. Mice were orally given a single dose of a modeling agent (MA) made of a mixture of schisandrin B/cholesterol/bile salts (1/2/0.5 g/kg) suspended in olive oil. MA treatment increased serum triglycerides (TG) and total cholesterol (TC) (up to 422% and 100% at 12 - 96 h post-treatment, respectively) and hepatic TG and TC (up to 220% and 26%, respectively) in a time- and dose-dependent manner, associated with elevation of high-density lipoprotein and low-density lipoprotein levels. Serum alanine/aspartate aminotransferase activities, indicators of liver cell damage, were also elevated (up to 198%) at 48 and 72 h post-MA treatment. Fenofibrate blocks MA-induced hyperlipidemia, lipid accumulation in the liver, as well as liver injury. Oral administration of a mixture of schisandrin B, cholesterol, and bile salt could generate an interesting mouse model of combined hyperlipidemia associated with hepatic steatosis and steatohepatitis.Journal of Pharmacological Sciences 10/2013; 123(2). DOI:10.1254/jphs.13087FP · 2.11 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Nonalcoholic steatohepatitis (NASH) is a progressive form of nonalcoholic fatty liver disease and a risk factor for cirrhosis, hepatocellular carcinoma and liver failure. Previously, we reported that dietary docosahexaenoic acid (DHA, 22:6,n-3) was more effective than eicosapentaenoic acid (EPA, 20:5,n-3) at reversing western diet (WD) induced NASH in LDLR(-/-) mice. Using livers from our previous study, we carried out a global non-targeted metabolomic approach to quantify diet-induced changes in hepatic metabolism. Livers from WD + olive oil (WD + O)-fed mice displayed histological and gene expression features consistent with NASH. The metabolomic analysis of 320 metabolites established that the WD and n-3 polyunsaturated fatty acid (PUFA) supplementation had broad effects on all major metabolic pathways. Livers from WD + O-fed mice were enriched in saturated (SFA) and monounsaturated fatty acids (MUFA), palmitoyl-sphingomyelin, cholesterol, n-6 PUFA, n-6 PUFA-containing phosphoglycerolipids, n-6 PUFA-derived oxidized lipids (12-HETE) and depleted of C20-22 n-3 PUFA-containing phosphoglycerolipids, C20-22 n-3 PUFA-derived oxidized lipids (18-HEPE, 17,18-DiHETE) and S-lactoylglutathione, a methylglyoxal detoxification product. WD + DHA was more effective than WD + EPA at attenuating WD + O-induced changes in NASH gene expression markers, n-6 PUFA and oxidized lipids, citrate and S-lactosyl glutathione. Diet-induced changes in hepatic MUFA and sphingolipid content were associated with changes in expression of enzymes involved in MUFA and sphingolipid synthesis. Changes in hepatic oxidized fatty acids and S-lactoylglutathione, however, correlated with hepatic n-3 and n-6 C20-22 PUFA content. Hepatic C20-22 n-3 PUFA content was inversely associated with hepatic α-tocopherol and ascorbate content and positively associated with urinary F2- and F3-isoprostanes, revealing diet effects on whole body oxidative stress. DHA regulation of hepatic SFA, MUFA, PUFA, sphingomyelin, PUFA-derived oxidized lipids and S-lactoylglutathione may explain the protective effects of DHA against WD-induced NASH in LDLR(-/-) mice.PLoS ONE 12/2013; 8(12):e83756. DOI:10.1371/journal.pone.0083756 · 3.53 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Nonalcoholic fatty liver disease (NAFLD) is a major public health concern in the obese and type 2 diabetic populations. The high fat lard diet (HFD) induces obesity and fatty liver in C57BL/6J mice and suppresses expression of the PPAR-target gene, fatty acid elongase-5 (Elovl5). Elovl5 plays a key role in MUFA and PUFA synthesis. Increasing hepatic Elovl5 activity in obese mice lowered hepatic triglyceride (TG) and endoplasmic reticulum stress markers (XBP-1, ATF6 alpha) and increased TG catabolism and fatty acyl carnitines. Increased hepatic Elovl5 activity did not increase hepatic capacity for beta oxidation. Elovl5 effects on hepatic TG catabolism were linked to increased protein levels of adipocyte triglyceride lipase (ATGL) and comparative gene identification-58 (CGI58). Elevated hepatic Elovl5 activity also induced the expression of some [pyruvate dehydrogenase kinase-4 [PDK4], fibroblast growth factor-21], but not other (CYP4A10) PPAR-target genes. Fatty acid products of Elovl5 activity increased ATGL, but not CGI58, mRNA through PPAR beta dependent mechanisms in human HepG2 cells. Treatment of mouse AML12 hepatocytes with the PPAR beta agonist (GW0742) decreased 14C-18:2,n-6 in triglycerides, but did not affect beta oxidation. These studies establish that Elovl5 activity regulates hepatic levels of fatty acids controlling PPAR beta activity, ATGL expression and TG catabolism, but not fatty acid oxidation.The Journal of Lipid Research 05/2014; 55(7). DOI:10.1194/jlr.M050062 · 4.73 Impact Factor