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.

Docosahexaenoic acid attenuates Western diet-induced hepatic fibrosis in Ldlr mice by targeting the TGFβ-Smad3 pathway

“…We also reported that adding EPA (20:5, 3) or DHA (22:6, 3) to the WD affected diet-induced hepatic fi brosis. DHA was more effective than EPA at attenuating WD-induced hepatic fi brosis ( 17,18,28 ). Although EPA and DHA attenuated WD-induced dyslipidemia, neither EPA nor DHA affected WD-induced body weight, the percent of body fat, blood glucose, or plasma endotoxin.…”

“…Omega-3 PUFAs have well-defi ned effects on hepatic lipid metabolism and infl ammation ( 29,73 ), and more recently their effects on hepatic fi brosis have been noted ( 17,28,69 ). Although several human studies have provided evidence in support of using supplemental 3 PUFAs to treat NAFLD (30)(31)(32)(33)(34)(35)(36)(37), other studies suggest there may be limitations for their use in NASH treatment ( 36,37 ).…”

“…In rodents, EPA and DHA suppress the expression of enzymes involved in PUFA synthesis ( 17 ). This mechanism involves the suppression of sterol regulatory element binding protein nuclear abundance ( 28 ), a key transcription factor regulating de novo lipogenesis and PUFA synthesis ( 29 ). As such, this mechanism lowers the capacity of cells to convert dietary C 18 -PUFA precursors to C 20-22 3 and 6 PUFAs.…”

“…A description of the diets and diet effects on mouse plasma and liver lipid composition was previously reported ( 17 ). At the end of the 16 week feeding period, all mice were fasted overnight (18:00 to 08:00 the next day) and euthanized at 08:00 for the collection of blood and liver ( 17,28 ).…”

A Novel Mouse Model of Combined Hyperlipidemia Associated With Steatosis and Liver Injury by a Single-Dose Intragastric Administration of Schisandrin B/Cholesterol/Bile Salts Mixture

“…In the present study, a mouse model of combined hyperlipidemia (i.e., hypertriglyceridemia/ hypercholesterolemia) was created by a single intragas tric administration of a mixture of Sch B, cholesterol (Ch), and a bile salt (Bs) suspended in olive oil. As hepatosteatosis is often associated with liver damage (14), we also examined the effects of the mouse model of dyslipidemia on liver damage.…”