Lowering n-6/n-3 Ratio as an Important Dietary Intervention to Prevent LPS-Inducible Dyslipidemia and Hepatic Abnormalities in ob/ob Mice

Abstract

Obesity is closely associated with low-grade chronic and systemic inflammation and dyslipidemia, and the consumption of omega-3 polyunsaturated fatty acids (n-3 PUFAs) may modulate obesity-related disorders, such as inflammation and dyslipidemia. An emerging research question is to understand the dietary intervention strategy that is more important regarding n-3 PUFA consumption: (1) a lower ratio of n-6/n-3 PUFAs or (2) a higher amount of n-3 PUFAs consumption. To understand the desirable dietary intervention method of n-3 PUFAs consumption, we replaced lard from the experimental diets with either perilla oil (PO) or corn oil (CO) to have identical n-3 amounts in the experimental diets. PO had a lower n-6/n-3 ratio, whereas CO contained higher amounts of PUFAs; it inherently contained relatively lower n-3 but higher n-6 PUFAs than PO. After the 12-week dietary intervention in ob/ob mice, dyslipidemia was observed in the normal chow and CO-fed ob/ob mice; however, PO feeding increased the high density lipoprotein-cholesterol (HDL-C) level; further, not only did the HDL-C level increase, the low density lipoprotein-cholesterol (LDL-C) and triglyceride (TG) levels also decreased significantly after lipopolysaccharide (LPS) injection. Consequently, extra TG accumulated in the liver and white adipose tissue (WAT) of normal chow- or CO-fed ob/ob mice after LPS injection; however, PO consumption decreased serum TG accumulation in the liver and WAT. PUFAs replacement attenuated systemic inflammation induced by LPS injection by increasing anti-inflammatory cytokines but inhibiting pro-inflammatory cytokine production in the serum and WAT. PO further decreased hepatic inflammation and fibrosis in comparison with the ND and CO. Hepatic functional biomarkers (aspartate aminotransferase (AST) and alanine transaminase (ALT) levels) were also remarkably decreased in the PO group. In LPS-challenged ob/ob mice, PO and CO decreased adipocyte size and adipokine secretion, with a reduction in phosphorylation of MAPKs compared to the ND group. In addition, LPS-inducible endoplasmic reticulum (ER) and oxidative stress decreased with consumption of PUFAs. Taken together, PUFAs from PO and CO play a role in regulating obesity-related disorders. Moreover, PO, which possesses a lower ratio of n-6/n-3 PUFAs, remarkably alleviated metabolic dysfunction in LPS-induced ob/ob mice. Therefore, an interventional trial considering the ratio of n-6/n-3 PUFAs may be desirable for modulating metabolic complications, such as inflammatory responses and ER stress in the circulation, liver, and/or WAT.

Molecular Mechanism for Hepatic Glycerolipid Partitioning of n-6/n-3 Fatty Acid Ratio in an Obese Animal Biomodels

“…On the contrary, lower n-6/n-3 can prevent obesity. According to the WHO, an ideal ratio of n-6/n-3 for human health is 4:1, which is recommended to be named as natural food [ 28 , 29 , 30 ].…”

“…These labeling lipids, cholesterol ester transfer protein and reaction reagents were then added to test tubes, cultured and labelled for lipoprotein to produce LPS. LPS was filtered using a filter (pore size: 0.45 μm) before use [ 10 , 11 , 29 ].…”

Glucose-Dependent Insulinotropic Polypeptide Plasma Level Influences the Effect of n-3 PUFA Supplementation

“…A detailed plasma fatty acids analysis indicated favorable changes in the high GIP group after n-3 PUFA supplementation, in terms of a decreased saturated / unsaturated FA ratio and a reduced amount of particular saturated FAs (myristic, palmitic, stearic) along with an increase in n-3 PUFAs and an n-6 PUFA decrease. Lowering the n-6/ n-3 FA ratio has recently been underlined as an important dietary intervention to prevent LPS-inducible dyslipidemia in an animal model [ 32 ]. Thus, the effect observed in obese patients with high GIP levels suggests a beneficial outcome.…”

Partial replacement of high-fat diet with n-3 PUFAs enhanced beef tallow attenuates dyslipidemia and endoplasmic reticulum stress in tunicamycin-injected rats

“…Chemiluminescence was detected using a Danvich Chemi Fluoro Imager (Danvich-K, Seoul, Korea). Visualization of the detected proteins were analyzed using ImageJ software (v.1.8 National Institutes of Health, Bethesda, MD, USA), with GAPDH as an internal control ( 34 ). Details of antibodies used for western blot analysis is listed in Table 5 .…”

“…We hypothesize that partial replacement of dietary fat with PUFAs could be an effective and reasonable strategy to reduce or prevent the incidence of MetS. Diets containing a lower ratio of n -6/ n -3 PUFAs appear to be more beneficial in mitigating the development of MetS; this can be applicable by adjusting to a reasonable balance, the intake of n -6 and n -3 ( 33 , 34 ). To this end, we partially replaced the fatty acids in high-fat and high-cholesterol diet (HFCD) with either regular BT or a n -3 enhanced BT, to investigate whether a dietary intervention could alleviate the MetS induced by the HFCD diet.…”