Summary The liver plays a key role in lipid metabolism. Depending on species it is, more or less, the hub of fatty acid synthesis and lipid circulation through lipoprotein synthesis. Eventually the accumulation of lipid droplets into the hepatocytes results in hepatic steatosis, which may develop as a consequence of multiple dysfunctions such as alterations in β‐oxidation, very low density lipoprotein secretion, and pathways involved in the synthesis of fatty acids. In addition an increased circulating pool of non‐esterified fatty acid may also to be a major determinant in the pathogenesis fatty liver disease. This review also focuses on transcription factors such as sterol‐regulatory‐element‐binding protein‐1c and peroxisome proliferator‐activated receptor alpha, which promote either hepatic fatty acid synthesis or oxidation.

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The occurrence and severity of obesity-and insulin resistance-related disorders vary according to the diet. The aim of the present longitudinal study was to examine the effects of a high-fat or a high-fructose diet on body weight (BW), body fat mass, insulin sensitivity (IS) and lipid profiles in a rat model of dietary-induced obesity and low IS. A total of eighteen, 12-week-old male Wistar rats were divided into three groups, and were fed with a control, a high-fat (65 % lipid energy) or a high-fructose diet (65 % fructose energy) for 10 weeks. BW, body fat mass ( 2 H 2 O dilution method), IS (euglycaemic -hyperinsulinaemic clamp technique), plasma glucose, insulin, NEFA, TAG and total cholesterol were assessed before and at the end of 10-week period. Cholesterol was measured in plasma lipoproteins separated from pooled samples of each group and each time period by using fast-protein liquid chromatography. All rats had similar BW at the end of the 10-week period. Body fat mass was higher in the high-fat group compared to the control group. There was no change in basal glycaemia and insulinaemia. The IS was lower in the high-fat group and was unchanged in the high-fructose group, compared to the control group. Plasma TAG concentration and cholesterol distribution in lipoproteins did not change over time in any group. Plasma NEFA concentration decreased, whereas plasma TAG concentration increased over time, regardless of the diet in both cases. The 10-week high-fat diet led to obesity and low IS, whereas rats fed with the high-fructose diet exhibited no change in IS and lipidaemia. The high-fat diet had more deleterious response than high-fructose diet to induce obesity and low IS in rats.Key words: insulin resistance: obesity: dyslipidemia: high-fat diet: high-fructose diet: rat There is a growing prevalence of obesity and low insulin sensitivity (IS), often called insulin resistance, in human subjects. Thus, there is a need for an animal model to study the time course of these metabolic disturbances as well as their unhealthy consequences. Different animal models have been used to study obesity and IS, notably the rat, in which obesity can be caused by genetic mutations or induced by nutritional interventions. As human obesity is mainly due to nutritional habits, animal models of obesity and low IS induced by specific diets may be preferable to genetic models.Various nutritional interventions have been used to induce obesity, low IS and dyslipidaemia in rats. High-fat diets have been shown to cause these metabolic disorders in previous studies, but there has been a large variability in the intensity of the metabolic changes (1 -5) . High-fructose diets have also been shown to lower IS and promote mild-to-severe dyslipidaemia (6 -9) . The differences in nutritional interventions, such as diet composition and interventional duration, have complicated the comparisons of these studies. Therefore, it is difficult to define the best nutritional intervention to induce obesity in an animal model that closely ...

Various strategies have been developed to increase the cellular level of (n-3) polyunsaturated fatty acids in animals and humans. In the present study, we investigated the effect of dietary myristic acid, which represents 9% to 12% of fatty acids in milk fat, on the storage of a-linolenic acid and its conversion to highly unsaturated (n-3) fatty acid derivatives. Five isocaloric diets were designed, containing equal amounts of a-linolenic acid (1.3% of dietary fatty acids, i.e. 0.3% of dietary energy) and linoleic acid (7.0% of fatty acids, i.e. 1.5% of energy). Myristic acid was supplied from traces to high levels (0%, 5%, 10%, 20% and 30% of fatty acids, i.e. 0% to 6.6% of energy). To keep the intake of total fat and other saturated fatty acids constant, substitution was made with decreasing levels of oleic acid (76.1% to 35.5% of fatty acids, i.e. 16.7% to 7.8% of energy) that is considered to be neutral in lipid metabolism. After 8 weeks, results on physiological parameters showed that total cholesterol and low-density lipoprotein-cholesterol did not differ in the diets containing 0%, 5% and 10% myristic acid, but were significantly higher in the diet containing 30% myristic acid. In all the tissues, a significant increasing effect of the substitution of oleic acid for myristic acid was shown on the level of both a-linolenic and linoleic acids. Compared with the rats fed the diet containing no myristic acid, docosahexaenoic acid significantly increased in the brain and red blood cells of the rats fed the diet with 30% myristic acid and in the plasma of the rats fed the diet with 20% myristic acid. Arachidonic acid also increased in the brain of the rats fed the diet with 30% myristic acid. By measuring D6-desaturase activity, we found a significant increase in the liver of the rats fed the diet containing 10% of myristic acid but no effect at higher levels of myristic acid. These results suggest that an increase in dietary myristic acid may contribute in increasing significantly the tissue storage of a-linolenic acid and the overall bioavailability of (n-3) polyunsaturated fatty acids in the brain, red blood cells and plasma, and that mechanisms other than the single D6-desaturase activity are involved in this effect.

Among obesity-associated disorders, low-grade inflammation has been described. The putative therapeutic properties of citrus and curcumin polyphenols could be associated with their anti-inflammatory properties. Two diets supplemented either with hesperidin (0·05 %) and naringin (0·1 %) from citrus extract or with highly bioavailable curcumin from Curcuma longa extract (0·09 %) were fed to eight obese cats for two 8-week periods (cross-over study design) while maintaining animals in an obese state. Plasma acute-phase protein (APP; a1-acid glycoprotein (AGP), serum amyloid A and haptoglobin) levels were assessed before and at the end of each test period. TNF-a, IL-1b, IL-2, IL-4, IL-5, IL-10, IL-12, IL-18, transforming growth factor-b, interferon (IFN)-g mRNA levels were determined in peripheral blood mononuclear cells (PBMC) by real-time PCR. Compared with pre-study values, supplementation with citrus polyphenols resulted in lower plasma AGP and haptoglobin concentrations, while that with curcumin resulted in lower plasma AGP concentration. There were no differences between the supplementations. TNF-a, IL-1b, IL-4, IL-5, IL-10, IL-12, IL-18, transforming growth factor-b, mRNA levels remained unaffected by either dietary supplementation. In contrast, IFN-g and IL-2 mRNA levels were lower at the end of the citrus and the curcumin supplementation, respectively. There were no differences between the supplementations. The present study results show a slight effect of citrus and curcumin supplementation on inflammatory markers expressed by PBMC, and a decreased concentration of APP, which are mainly expressed by the liver. This would confirm that hesperidin and naringin or highly bioavailable curcumin extract have beneficial effects, targeted in the liver and could improve the obesity-related inflammatory state.

Dihydroceramide Δ4-desaturase 1 (DES1) catalyzes the last step of the de novo ceramide biosynthesis, which consists of the introduction of a trans Δ4-double bond in the carbon chain of the dihydroceramide. It was previously observed that myristic acid binds DES1 through N-myristoylation. This N-terminal modification significantly increased the activity of the recombinant DES1 in COS-7 cells and targeted part of the enzyme initially present in the endoplasmic reticulum to the mitochondrial outer membrane, leading to an increase in ceramide levels. Since these results were obtained in a recombinant COS-7 cell model with high expression of rat DES1, the purpose of the present study was to investigate if the native DES1 enzyme was really upregulated by its N-myristoylation in cultured rat hepatocytes. We first showed that DES1 was the main dihydroceramide desaturase isoform expressed in rat hepatocytes. In this model, the wild-type myristoylable recombinant form of rat DES1 was found in both the endoplasmic reticulum and the mitochondria whereas the mutated non-myristoylable recombinant form (N-terminal glycine replaced by an alanine) was almost exclusively localized in the endoplasmic reticulum, which evidenced the importance of the myristoylation. Then, we showed that compared to other fatty acids, myristic acid was the only one to increase native DES1 activity, in both total cell lysates and mitochondrial fractions. The myristic acid-associated increase in DES1 activity was not linked to elevated mRNA or protein expression but more likely to its N-terminal myristoylation. Finally, the myristic acid-associated increase in DES1 activity slightly enhanced the number of apoptotic cells.

Apolipoprotein B100 (apoB100) is an essential component of very low density lipoprotein (VLDL) and low-density lipoprotein (LDL), both independent markers of cardiovascular risk. Nicotinic acid (NA) is an efficacious drug for decreasing VLDL and LDL, but the underlying mechanisms are unclear. For this purpose, six obese insulin-resistant dogs were given 350 mg/day of NA for 1 week and then 500 mg/day for 3 weeks. Turnover of apoB100-containing lipoproteins was investigated using stable isotope-labeled tracers. Multicompartmental modeling was used to derive kinetic parameters before and at the end of NA treatment. Hepatic diacylglycerol acyltransferase 2 (DGAT2), microsomal triglyceride transfer protein (MTP), hepatic lipase (HL), and adipose lipoprotein lipase (LPL) mRNA expression was also determined. NA treatment decreased plasma triglyceride (TG) (p Ͻ 0.001), VLDL-TG (p Ͻ 0.05), total cholesterol (p Ͻ 0.0001), and LDL cholesterol (p Ͻ 0.05), whereas plasma nonesterified fatty acids were unchanged. The decrease in VLDL-apoB100 concentration (p Ͻ 0.001) was the result of a lower absolute production rate (APR) (p Ͻ 0.001), despite a moderate decrease (p Ͻ 0.05) in fractional catabolic rate (FCR). LDLapoB100 concentration was reduced (p Ͻ 0.05), an effect related to a decrease in LDL APR (p Ͻ 0.05) and no change in FCR. NA treatment reduced DGAT2 expression (p Ͻ 0.05), whereas MTP, HL, and LPL expression was unchanged. Our results suggest that NA treatment reduced VLDL and LDL concentration as a consequence of a decrease in VLDL production.