Regulatory Effects And Underlying Mechanism Of Flaxseed Lignan On Obesity-Related-Lipid Metabolism Disorders

The westernization of dietary patterns has precipitated a sharp increase in obesity and its complications including diabetes,cardiovascular disease,atherosclerosis and nonalcoholic fat liver disease(NAFLD),which have posed a serious threat to human health worldwide.Thus,there is an urgent requirement to find molecular targets related to the treatment of obesity-related chronic metabolic diseases.In recent years,the exploration of food functional components that may improve obesity and its complications has become an important research direction in food nutrition field.Secoisolariciresinol diglucoside(SDG),a natural phytochemical primarily derived from flaxseed,has been shown to have a positive effect on obesity-related metabolic diseases.However,only a few reports have focused on its potential molecular mechanisms on regulating obesity-related metabolic abnormalities.It has been reported that the endoplasmic reticulum(ER)and mitochondria are critical organelles in regulating abnormal lipid metabolism.ER is an important site for the synthesis of membrane lipids and cholesterol.As the main site of oxidative metabolism in eukaryotes,mitochondria play a significant role in fatty acid?-oxidation.Recent studies have shown that abnormal exchange of Ca²⁺between endoplasmic reticulum and mitochondria is associated with the pathogenesis insulin resistance and hepatic steatosis during obesity.Thus,the ER-mitochondrial axis may be the valuable target area for the prevention and treatment of obesity and its complications.In the current study,the natural phytochemical SDG were selected as the research object,the regulation effects of SDG on obesity-related lipid metabolism disorders caused by high-calorie diet and its potential mechanism were explored by constructing animal and cell models.The experimental results are as follows:(1)C57BL/6J mice were treated with HFFD and SDG.To investigate the effect of dietary intake of SDG on basic metabolic parameters of HFFD-induced obese mice,the body weight,body fat mass,serum metabolic parameters and other basic physiological indicators of mice in each group were detected.The results showed that the intake of SDG reduced the bodyweight gain of HFFD mice,improved glucose intolerance and insulin resistance in HFFD mice,and balanced serum adipokine levels and lipid contents in HFFD mice.(2)Liver and adipose tissue were selected as the main research objects.To investigate the effect of SDG supplementation on the regulation of abnormal lipid metabolism in HFFD mice and its underlying mechanism,H&E staining,immunohistochemical staining,q RT-PCR and other means were implemented.The results suggested that the intake of SDG reduced the increase of tissue weight to body weight in HFFD mice,reduced the level of hepatic lipid contents in HFFD mice,and inhibited the accumulation of lipid droplets and expansion of adipose tissue in HFFD mice.And,the lipid metabolism disorder in HFFD mice was improved by up-regulating the expression of lipid oxidation-related genes and down-regulating the expression of genes related to lipid synthesis.(3)Hepatic ER and mitochondria were selected as the main research objects.To analyze the effect of SDG supplementation on hepatic ER and mitochondrial structure,ER-mitochondrial contact,ER stress and mitochondrial dysfunction in HFFD mice,transmission electron microscopy(TEM)observation and q RT-PCR were performed.It was found that the addition of SDG improved the abnormalities of ER and mitochondrial structure in the liver of HFFD mice,reduced the excessive coupling of ER-mitochondria in HFFD mice,ameliorated ER stress and mitochondrial dysfunction in HFFD mice.(4)Lipid metabolism disorder model was constructed in Hep G2 cells.To investigate the intervening effect of SDG on palmitic acid(PA)-induced lipid metabolism disorder in Hep G2 cells and its potential mechanism related to ER-mitochondrial axis,oil red O staining,mitochondrial membrane potential detection(JC-1 staining),and Ca²⁺fluorescent probe detection(Fluo-4AM and Rhod-2AM staining)was performed.The results indicated that SDG inhibited PA-induced abnormal lipid accumulation in Hep G2 cells by reducing ER stress,lessening Ca²⁺levels,and improving mitochondrial dysfunction.In summary,dietary supplementation of SDG effectively improved HFFD-induced lipid metabolism disorders by intervening in the ER stress-Ca2+-mitochondria related pathway.The present study could provide a theoretical basis for the development of healthy foods with SDG as a major functional ingredient and could provide new strategies for nutritional intervention studies of other natural functional food components on high-calorie diets induced obesity and its complications.