It has been demonstrated in animal studies that both polyphenol-rich pomegranate extract (PomX) and the polysaccharide inulin, ameliorate metabolic changes induced by a high-fat diet, but little is known about the specific mechanisms.

The present study investigated the role of dietary cholesterol and fat in the development of nonalcoholic fatty liver disease, a common liver disease in metabolic disorders. Mice were fed a diet of regular chow (CH), chow supplemented with 0.2% w/w cholesterol (CHC), high fat (HF, 45kcal%) or HF with cholesterol (HFC) for 17weeks. While both HF and HFC groups displayed hepatic steatosis and metabolic syndrome, only HFC group developed the phenotype of liver injury, as indicated by an increase in plasma level of alanine transaminase (ALT, by 50-80%). There were ~2-fold increases in mRNA expression of tumor necrosis factor α, interleukin 1β and monocyte chemotactic protein 1 in the liver of HFC-fed mice (vs. HF) but no endoplasmic reticulum stress or oxidative stress was observed. Furthermore, cholesterol suppressed HF-induced increase of peroxisome proliferator-activated receptor γ coactivator 1α and mitochondrial transcription factor A expression and blunted fatty acid oxidation. Interestingly, after switching HFC to HF diet for 5weeks, the increases in plasma ALT and liver inflammatory markers were abolished but the blunted of mitochondrial function remained. These findings suggest that cholesterol plays a critical role in the conversion of a simple fatty liver toward nonalcoholic steatohepatitis possibly by activation of inflammatory pathways together with retarded mitochondrial function.

Interesterified fats are currently being used to replace trans fatty acids. However, their impact on biological pathways involved in the atherosclerosis development was not investigated. Weaning male LDLr-KO mice were fed for 16weeks on a high-fat diet (40% energy as fat) containing polyunsaturated (PUFA), TRANS, palmitic (PALM), palmitic interesterified (PALM INTER), stearic (STEAR) or stearic interesterified (STEAR INTER). Plasma lipids, lipoprotein profile, arterial lesion area, macrophage infiltration, collagen content and inflammatory response modulation were determined. Macrophage cholesterol efflux and the arterial expression of cholesterol uptake and efflux receptors were also performed. The interesterification process did not alter plasma lipid concentrations. Although PALM INTER did not increase plasma cholesterol concentration as much as TRANS, the cholesterol enrichment in the LDL particle was similar in both groups. Moreover, PALM INTER induced the highest IL-1β, MCP-1 and IL-6 secretion from peritoneal macrophages as compared to others. This inflammatory response elicited by PALM INTER was confirmed in arterial wall, as compared to PALM. These deleterious effects of PALM INTER culminate in higher atherosclerotic lesion, macrophage infiltration and collagen content than PALM, STEAR, STEAR INTER and PUFA. These events can partially be attributed to a macrophage cholesterol accumulation, promoted by apoAI and HDL2-mediated cholesterol efflux impairment and increased Olr-1 and decreased Abca1 and Nr1h3 expressions in the arterial wall. Interesterified fats containing palmitic acid induce atherosclerosis development by promoting cholesterol accumulation in LDL particles and macrophagic cells, activating the inflammatory process in LDLr-KO mice.

To compare the relative impact of trans-18:1 with the two main dietary saturated fatty acids it replaces, plasma lipid response was assessed in Mongolian gerbils fed diets rich in 16:0 (24%en),18:0 (10%en), or trans-18:1 (4 or 6%en). The diets were designed such that the 18:0-rich diet substituted 7%en as 18:0 for 16:0, whereas 4%en and 6%en from trans-18:1 was substituted for 16:0 in the two trans diets. The control group was fed a diet formulated according to the fatty acid balance of American Heart Association (AHA), but provided 40%en as fat. Gerbils (n = 10 per dietary group) were fed one of the five diets for 8 weeks. The control diet, with 4 times the polyunsaturated fatty acids (PUFA) content and a P:S ratio about 10 times greater than the test diets, resulted in the lowest plasma TC, LDL cholesterol (LDL-C) and VLDL cholesterol (VLDL-C). Among the test diets, plasma TC and TG were lowest with the 18:0-rich diet. TC in gerbils fed the 16:0-rich diet and 4%en-trans were 20% higher than the 18:0-rich diet, while the 6%en-trans diet was 35% higher. VLDL-C was significantly higher in the 6%en-trans diet compared to all other groups at 8 weeks. Both trans fatty acid diets elevated plasma TG approximately 2- and 3-fold, respectively, compared to the 16:0-rich and 18:0-rich diets at 8 weeks. Further, plasma TG continued to rise over time with trans fatty acids compared to 16:0 or 18:0. Thus, in the fatty acid-sensitive gerbil, impaired TG metabolism represents a major aspect of the hyperlipemia caused by trans fatty acid substitution for major saturated fatty acids.

The aim of this study was to determine the impact of dietary plant sterols and stanols on sterol incorporation and sterol-regulatory gene expression in insulin-treated diabetic rats and nondiabetic control rats. Diabetic BioBreeding (BB) and control BB rats were fed a control diet or a diet supplemented with plant sterols or plant stanols (5 g/kg diet) for 4 weeks. Expression of sterol-regulatory genes in the liver and intestine was assessed by real-time quantitative polymerase chain reaction. Diabetic rats demonstrated increased tissue accumulation of cholesterol and plant sterols and stanols compared to control rats. This increase in cholesterol and plant sterols and stanols was associated with a marked decrease in hepatic and intestinal Abcg5 (ATP-binding cassette transporter G5) and Abcg8 (ATP-binding cassette transporter G8) expressions in diabetic rats, as well as decreased mRNA levels of several other genes involved in sterol regulation. Plant sterol or plant stanol supplementation induced the accumulation of plant sterols and stanols in tissues in both rat strains, but induced a greater accumulation of plant sterols and stanols in diabetic rats than in control rats. Surprisingly, only dietary plant sterols decreased cholesterol levels in diabetic rats, whereas dietary plant stanols caused an increase in cholesterol levels in both diabetic and control rats. Therefore, lower expression levels of Abcg5/Abcg8 in diabetic rats may account for the increased accumulation of plant sterols and cholesterol in these rats.

Choline is an essential nutrient required for various biological processes. Eggs, dairy, and meat are rich in phosphatidylcholine (PC), whereas cereal and legumes are rich in free choline. Excess dietary choline leads to increase plasma trimethylamine N-oxide (TMAO). Epidemiological studies suggest that plasma TMAO is a biomarker for atherosclerosis and it has been suggested that a lower intake of eggs and meat would reduce choline consumption and thus reduce atherosclerosis development. To investigate whether the form of dietary choline influences atherosclerosis development in Ldlr-/-, we randomly fed Ldlr-/-male mice (aged 8 - 10 wk) one of the three 40% (calories) high fat diets (with 0.5% w/w of cholesterol): Control (0.1% w/w free-choline, CON), choline-supplemented (0.4% free-choline, CS), or PC-supplemented (0.1% free-choline and 0.3% choline from PC, PCS). After 12-wk of dietary intervention, the animals were euthanized and tissues and blood collected. Aortic atherosclerotic plaque area, plasma choline, lipid metabolites, and spleen and peripheral blood cell phenotypes were quantified. Surprisingly, the PCS group had significantly lower atherosclerotic lesions while having 2-fold higher plasma TMAO levels compared with both CON and CS groups (P<0.05). In the fasting state, we found that PCS decreased plasma very low-density lipoprotein-cholesterol (VLDL-C) and apolipoprotein B48 (APOB48), and increased plasma high-density lipoprotein-cholesterol (HDL-C). However, very low-density lipoprotein (VLDL) secretion was not affected by dietary treatment. We observed lower levels of circulating pro-atherogenic chemokines in the PCS group. Our study suggests that increased dietary PC intake does not induce a pro-atherogenic phenotype.

We investigated the effects of a saturated fat diet on mice lipid metabolism in resident peritoneal macrophages. Male C57BL/6 mice were weaned at 21 days of age and assigned to either the experimental diet, containing coconut oil (COCO diet), or the control diet, containing soybean oil as fat source. Fat content of each diet was 15% (w/w). Mice were fed for 6 weeks until sacrifice. In plasma of mice fed the COCO diet, the concentration of triglyceride, total cholesterol, HLD- and (LDL+VLDL)-cholesterol, and thiobarbituric acid-reactive substances (TBARS) increased, without changes in phospholipid concentration, compared with the controls. In macrophages of COCO-fed mice, the concentration of total (TC), free and esterified cholesterol, triglyceride, phospholipid (P) and TBARS increased, while the TC/P ratio did not change. The phospholipid compositions showed an increase of phosphatidylcholine and phosphatidylserine + phosphadytilinositol, a decrease of phosphatidylethanolamine, and no change in phosphatidylglycerol. (3)H(2)O incorporation into triglyceride and phospholipid fractions of macrophages increased, while its incorporation into free cholesterol decreased. Incorporation of [(3)H]cholesterol into macrophages of COCO-fed mice and the fraction of [(3)H]cholesterol ester increased. COCO diet produced an increase in myrystic, palmitic and palmitoleic acids proportion, a decrease in linoleic and arachidonic acids and no changes in stearic and oleic acids, compared with the control. Also, a higher relative percentage of saturated fatty acid and a decrease in unsaturation index (p <0.001) were observed in macrophages of COCO-fed mice. These results indicate that the COCO-diet, high in saturated fatty acids, alters the lipid metabolism and fatty acid composition of macrophages and produces a significant degree of oxidative stress.

Long-term dietary intake of elevated levels of refined sugars, fats and cholesterols is among the factors causing cognitive impairment. Ketone bodies can be used as an alternative energy source when glucose is not available. The study investigated the effects of a ketogenic diet (medium chain triglyceride, MCT) on cognitive performance after a long-term consumption of a high-fat-high-cholesterol diet using a mice model. Seventy eight-week-old male C57BL/6 mice were fed an HFHC diet for 16 weeks to establish a model of an HFHC dietary pattern, before receiving intervention diets containing MCT diet or with Metformin for another 8 weeks in the second part of the experiment. Spatial learning, memory performance, and cortical and hippocampal protein expression levels were assessed. After consuming the HFHC diet for 16 weeks and subsequently receiving the MCT diet for 8 weeks, results showed that the mice fed a MCT diet had significantly better spatial learning and memory performance, lower expression of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), tumor necrosis factor-α (TNF-α), glial fibrillary acidic protein (GFAP), amyloid protein precursor (APP) and phosphate tau, and higher expression of brain-derived neurotrophic factor (BDNF) than the mice fed the HFHC diet. Long-term consumption of an HFHC diet caused a decline in cognitive functions and increased the risk factors for neurodegeneration, such as BBB permeability, neuropathy and inflammation. An MCT diet can be considered as an option for slowing down the early stage of neurodegeneration in mice.

Disequilibrium of the gut microbiota by dietary fat has been implicated in the incidence of overweight or obesity. However, it remains to be elucidated whether dietary fat perturbations in early life have long-lasting impacts on the gut microbiota and to what extent unbalanced diet-induced alterations in childhood are reversible. Accordingly, three groups of 1-day-old hens were used. They were fed with a low-fat diet (LFD), basal diet (BD) and high-fat diet (HFD), respectively, for 6 weeks and then switched to the same normal diets (NDs) for another 19 weeks. At week 6, hens in the LFD and HFD groups were found to have higher body weight, plasma glucose, total cholesterol, triglycerides and low-density lipoprotein cholesterol levels than their counterparts in the BD group, whereas upon switching to NDs, the metabolic deteriorations observed during the LFD consumption were alleviated. Principal component analysis revealed a shift of the gut microbiota structure in the LFD and HFD groups away from that of the BD group at week 6, while the gut microbiota structure of the LFD group was moved back to that of the BD group after reverting to NDs. Additionally, abnormal alterations of obesity-related phylotypes were observed in the LFD and HFD groups, whereas the abundance of these phylotypes in the LFD group was almost reverted to the BD levels over time. Collectively, dietary fat perturbations in early life have long-term impacts on hosts, and the structural resilience of the gut microbiota in hens fed with HFD was lower than that in their LFD counterparts.

Optimizing diet quality in conjunction with statin therapy is currently the most common approach for coronary artery disease (CAD) risk management. Although effects on the cardiovascular system have been extensively investigated, little is known about the effect of these interventions in the colon and subsequent associations with CAD progression. To address this gap, Ossabaw pigs were randomly allocated to receive, for a six-month period, isocaloric amounts of either a heart healthy-type diet (HHD; high in unrefined carbohydrate, unsaturated fat, fiber, supplemented with fish oil, and low in cholesterol) or a Western-type diet (WD; high in refined carbohydrate, saturated fat and cholesterol, and low in fiber), without or with atorvastatin therapy. At the end of the intervention period, colon samples were harvested, mucosa fraction isolated, and RNA sequenced. Gene differential expression and enrichment analyses indicated that dietary patterns and atorvastatin therapy differentially altered gene expression, with diet-statin interactions. Atorvastatin had a more profound effect on differential gene expression than diet. In pigs not receiving atorvastatin, the WD upregulated "LXR/RXR Activation" pathway compared to pigs fed the HHD. Enrichment analysis indicated that atorvastatin therapy lowered inflammatory status in the HHD-fed pigs, whereas it induced a colitis-like gene expression phenotype in the WD-fed pigs. No significant association was identified between gene expression phenotypes and severity of atherosclerotic lesions in the left anterior descending-left circumflex bifurcation artery. These data suggested diet quality modulated the response to atorvastatin therapy in colonic mucosa, and these effects were unrelated to atherosclerotic lesion development.

Western-type diets can induce obesity and related conditions such as dyslipidemia, insulin resistance and hepatic steatosis. We evaluated the effects of milk sphingomyelin (SM) and egg SM on diet-induced obesity, the development of hepatic steatosis and adipose inflammation in C57BL/6J mice fed a high-fat, cholesterol-enriched diet for 10 weeks. Mice were fed a low-fat diet (10% kcal from fat) (n=10), a high-fat diet (60% kcal from fat) (HFD, n=14) or a high-fat diet modified to contain either 0.1% (w/w) milk SM (n=14) or 0.1% (w/w) egg SM (n=14). After 10 weeks, egg SM ameliorated weight gain, hypercholesterolemia and hyperglycemia induced by HFD. Both egg SM and milk SM attenuated hepatic steatosis development, with significantly lower hepatic triglycerides (TGs) and cholesterol relative to HFD. This reduction in hepatic steatosis was stronger with egg SM supplementation relative to milk SM. Reductions in hepatic TGs observed with dietary SM were associated with lower hepatic mRNA expression of PPARγ-related genes: Scd1 and Pparg2 in both SM groups, and Cd36 and Fabp4 with egg SM. Egg SM and, to a lesser extent, milk SM reduced inflammation and markers of macrophage infiltration in adipose tissue. Egg SM also reduced skeletal muscle TG content compared to HFD. Overall, the current study provides evidence of dietary SM improving metabolic complications associated with diet-induced obesity in mice. Further research is warranted to understand the differences in bioactivity observed between egg and milk SM.

Obesity induced by overfeeding ultimately can lead to nonalcoholic fatty liver disease, whereas dietary fiber consumption is known to have a beneficial effect. We aimed to determine if a supplementation of a mix of fibers (inulin, resistant starch and pectin) could limit or alleviate overfeeding-induced metabolic perturbations. Twenty female minipigs were fed with a control diet (C) or an enriched fat/sucrose diet supplemented (O + F) or not (O) with fibers. Between 0 and 56 days of overfeeding, insulin (+88%), HOMA (+102%), cholesterol (+45%) and lactate (+63%) were increased, without any beneficial effect of fibers supplementation. However, fibers supplementation limited body weight gain (vs. O, -15% at D56) and the accumulation of hepatic lipids droplets induced by overfeeding. This could be explained by a decreased lipids transport potential (-50% FABP1 mRNA, O + F vs. O) inducing a down-regulation of regulatory elements of lipids metabolism / lipogenesis (-36% SREBP1c mRNA, O + F vs. O) but not to an increased oxidation (O + F not different from O and C for proteins and mRNA measured). Glucose metabolism was also differentially regulated by fibers supplementation, with an increased net hepatic release of glucose in the fasted state (diet × time effect, P<.05 at D56) that can be explained partially by a possible increased glycogen synthesis in the fed state (+82% GYS2 protein, O + F vs. O, P=.09). The direct role of short chain fatty acids on gluconeogenesis stimulation is questioned, with probably a short-term impact (D14) but no effect on a long-term (D56) basis.

Connexins (Cx) and cadherins are responsible for cell homeostasis. The Cx activity is directly related to cholesterol. The present work investigates whether vitamin E, with or without caloric restriction (CR), alters the mRNA expression of Cx26, Cx32, Cx43, N-cadherins (N-cads), E-cadherins (E-cads) and alpha-smooth muscle actin (α-SMA), and evaluates their relation to cholesterol metabolism in rat liver. Animals were divided into different groups: control with ad libitum diet (C), control+vitamin E (CV), aloric restriction with intake to 60% of group C (CR), and the intake of group CR+vitamin E (RV). There were increases of manganese superoxide dismutase (Mn-SOD) and glutathione S-transferase mu 1, indicating antioxidant effects of CR and vitamin E. An increase of nitric oxide in the CR group was in agreement with the Mn-SOD data. Supplementation with vitamin E, with or without CR, upregulated the expression of Cx26 mRNA and increased low-density lipoprotein cholesterol (LDL-c) in the CV group. Reductions of Cx32 and Cx43 were associated with lower LDL-c. Increases in Hmgcr and low-density lipoprotein receptor (LDLr) in the CV and RV groups could be explained by the effect of vitamin E. A reduction of LDLr in the CR group was due to the reduced dietary intake. Increases in cadherins in the CV, CR and RV groups were indicative of tissue maintenance, which was also supported by increases of α-SMA in groups CV and RV. Finally, vitamin E, with or without CR, increased Cx26, probably modulated by expression of the Hmgcr and LDLr genes. This suggests important relationship of Cxs and cholesterol metabolism genes.

Cholesterol and its oxidative derivative 27-hydroxycholesterol (27-OHC), synthesized by CYP27A1, play an important role in Alzheimer's disease (AD) and phosphorylation of tau might be partly responsible for its pathogenesis. To investigate whether cholesterol and 27-OHC affected learning and memory through autophagy-mediated phosphorylation of tau, male C57BL/6J mice were administrated with 2% cholesterol diet, CYP27A1-short-hairpin RNA (CYP27A1-shRNA) and 3-methyladenine (3-MA). The results show that dietary cholesterol induces learning and memory impairment by upregulating the expression of brain CYP27A1 and increasing the levels of 27-OHC and 24S-hydroxycholesterol (24S-OHC). The expressions of total-tau (t-tau), phosphorylated-tau (p-tau) protein, glycogen synthase kinase-3β (GSK-3β) and cyclin-dependent kinase 5 (CDK5) are also significantly upregulated in this group. In addition, reduced expressions of Beclin-1 protein and microtubule-associated protein 1 light chain 3 (LC3B) mRNA, over-expression of mammalian target of rapamycin (mTOR) protein suggest that autophagy is impaired during cholesterol burden. However, using of CYP27A1-shRNA remarkably downregulates the expression of brain CYP27A1. Decreased 27-OHC levels in serum and brain, lower expressions of t-tau and p-tau protein are observed in mice treated with CYP27A1-shRNA+2% cholesterol diet. Furthermore, 3-MA causes lower Beclin-1, higher mTOR and p62 on both gene and protein levels, while the expression of t-tau, p-tau, GSK-3β and CDK5 are upregulated, demonstrating that impaired autophagy disturbs the clearance of tau. These findings suggest that dietary cholesterol induces the accumulation and phosphorylation of tau and the mechanism might be associated with impaired autophagy. And our results indicate 27-OHC might be an importance bridge between cholesterol and cognitive decline.

Copper (Cu) deficiency decreases the activity of Cu-dependent antioxidant enzymes such as Cu,zinc-superoxide dismutase (Cu,Zn-SOD) and may be associated with increased susceptibility to oxidative stress. Iron (Fe) overload represents a dietary oxidative stress relevant to overuse of Fe-containing supplements and to hereditary hemochromatosis. In a study to investigate oxidative stress interactions of dietary Cu deficiency with Fe overload, weanling male Long-Evans rats were fed one of four sucrose-based modified AIN-93G diets formulated to differ in Cu (adequate 6 mg/kg diet vs. deficient 0.5 mg/kg) and Fe (adequate 35 mg/kg vs. overloaded 1500 mg/kg) in a 2 x 2 factorial design for 4 weeks prior to necropsy. Care was taken to minimize oxidation of the diets prior to feeding to the rats. Liver and plasma Cu content and liver Cu,Zn-SOD activity declined with Cu deficiency and liver Fe increased with Fe overload, confirming the experimental dietary model. Liver thiobarbituric acid reactive substances were significantly elevated with Fe overload (pooled across Cu treatments, 0.80+/-0.14 vs. 0.54+/-0.08 nmol/mg protein; P<.0001) and not affected by Cu deficiency. Liver cytosolic protein carbonyl content and the concentrations of several oxidized cholesterol species in liver tissue did not change with these dietary treatments. Plasma protein carbonyl content decreased in Cu-deficient rats and was not influenced by dietary Fe overload. The various substrates (lipid, protein and cholesterol) appeared to differ in their susceptibility to the in vivo oxidative stress induced by dietary Fe overload, but these differences were not exacerbated by Cu deficiency.

Epicardial adipose tissue (EAT) inflammation is thought to potentiate the development of coronary artery disease (CAD). Overall diet quality and statin therapy are important modulators of inflammation and CAD progression. Our objective was to examine the effects and interaction of dietary patterns and statin therapy on EAT gene expression in the Ossabaw pig. Pigs were randomized to 1 of 4 groups; Heart Healthy diet (high in unsaturated fat, unrefined grain, fruits/vegetables [HHD]) or Western diet (high in saturated fat, cholesterol, refined grain [WD]), with or without atorvastatin. Diets were fed in isocaloric amounts for 6 months. A two-factor edge R analysis identified the differential expression of 21 genes. Relative to the HHD, the WD resulted in a significant 12-fold increase of radical s-adenosyl methionine domain containing 2 (RSAD2), a gene induced by interferon signaling. Atorvastatin led to the significant differential expression of 17 genes predominately involved in interferon signaling. Results were similar using the Porcine Translational Research Database. Pathway analysis confirmed the up-regulation of interferon signaling in response to the WD and atorvastatin independently. An expression signature of the largely interferon related differentially expressed genes had no predictive capability on a histological assessment of atherosclerosis in the underlying coronary artery. These results suggest that a WD and atorvastatin evoke an interferon mediated immune response in EAT of the Ossabaw pig, which is not associated with the presence of atherosclerosis.

Previous studies suggest that dietary salecan (a water-soluble β-glucan) effectively reduces high-fat-diet-induced adiposity through disturbing bile-acid-promoted emulsification in mice. However, the effects of salecan on metabolic genes and metabolites involved in lipid accumulation are mostly unknown. Here, we confirmed that dietary 3% and 6% salecan for 4 weeks markedly decreased fat accumulation in liver and adipose tissue in high-fat-diet rats, displaying a decrease in mRNA levels of SREBP1-C, FAS, SCD1 and ACC1 involved in de novo lipogenesis and a reduction of levels of GPAT1, DGAT1 and DGAT2 related to triglyceride synthesis. Dietary salecan also increased the mRNA levels of PPARα and CYP7A1, which are related to fatty acid oxidation and cholesterol decomposition, respectively. In the 1H nuclear magnetic resonance metabolomic analysis, both the serum and liver metabolite profiles differed among the control groups, and the metabolic profiles of the salecan groups were shifted toward that of the low-fat-diet group. Metabolites analysis showed that salecan significantly increased hepatic glutathione and betaine levels which are related to regulation of cellular reactive oxygen species. These data demonstrate that dietary salecan not only disturbed fat digestion and absorption but also influenced lipid accumulation and metabolism in diet-induced obesity.

We sought to determine whether a combination of purified n-3 fatty acids (n-3) and SC-560 (SC), a cyclooxygenase-1-specific inhibitor, is effective in ameliorating nonalcoholic fatty liver disease in obesity. Female wild-type mice were fed a high-fat and high-cholesterol diet (HF) supplemented with n-3 in the presence or absence of SC. Mice treated with SC alone exhibited no change in liver lipids, whereas n-3-fed mice tended to have lower hepatic lipids. Mice given n-3+SC had significantly lower liver lipids compared with HF controls indicating enhanced lipid clearance. Total and sulfated bile acids were significantly higher only in n-3+SC-treated mice compared with chow diet (CD) controls. Regarding mechanisms, the level of pregnane X receptor (PXR), a nuclear receptor regulating drug/bile detoxification, was significantly higher in mice given n-3 or n-3+SC. Studies in precision-cut liver slices and in cultured hepatoma cells showed that n-3+SC enhanced not only the expression/activation of PXR and its target genes but also the expression of farnesoid X receptor (FXR), another regulator of bile synthesis/clearance, indicating that n-3+SC can induce both PXR and FXR. The mRNA level of FGFR4 which inhibits bile formation showed a significant reduction in Huh 7 cells upon n-3 and n-3+SC treatment. PXR overexpression in hepatoma cells confirmed that n-3 or SC each induced the expression of PXR target genes and in combination had an enhanced effect. Our findings suggest that combining SC with n-3 potentiates its lipid-lowering effect, in part, by enhanced PXR and/or altered FXR/FGFR4 signaling.

An olive oil (OO) rich diet or high-intensity interval training (HIIT) independently improve markers of health and energy metabolism, but it is unknown if combining OO and HIIT synergize to improve these markers. This study characterized the isolated and combined impact of OO and HIIT on markers of health and energy metabolism in various tissues in C57BL/6J female mice. Nine-week-old mice were divided into four groups for a 12-week diet and/or exercise intervention including: (1) Control Diet without HIIT (CD), (2) Control Diet with HIIT (CD+HIIT), (3) OO diet (10% kcal from olive oil) without HIIT, and (4) OO diet with HIIT (OO+HIIT). Neither dietary OO or HIIT altered body weight, glucose tolerance, or serum lipids. HIIT, regardless of diet, increased aerobic capacity and HDL cholesterol levels. In liver and heart tissue, OO resulted in similar adaptations as HIIT including increased mitochondrial content and fatty acid oxidation but combining OO with HIIT did not augment these effects. In skeletal muscle, HIIT increased mitochondrial content in type II fibers similarly between diets. An RNA sequencing analysis on type I fibers revealed OO reduced muscle regeneration and lipid metabolism gene abundance, whereas HIIT increased the abundance of these genes, independent of diet. HIIT training, independent of diet, induced subcutaneous white adipose tissue (sWAT) hypertrophy, whereas OO induced gonadal white adipose tissue (gWAT) hypertrophy, an effect that was augmented with HIIT. These data highlight the pleiotropic effects of OO and HIIT, although their combination does not synergize to further improve most markers of health and energy metabolism.

The intermittent fasting (IF) might have benefits on metabolism and food intake. Twelve-week old C57BL/6 J mice were fed a control diet (C, 10% kcal fat), a high-fat diet (HF, 50% kcal fat) or a high-fructose diet (HFru, 50% kcal fructose) for 8 weeks, then half of the animals in each group underwent IF (24 h fed, 24 h fasting) for an additional 4 weeks. Although food intake on the fed day remained the same for all groups, all fasting groups showed a reduction in body mass compared to their counterparts. IF reduced total cholesterol, triacylglycerol, fasting glucose, fasting insulin resistance index, and plasma leptin, but increased plasma adiponectin. IF reduced Leptin gene expression in the HF-IF group, but increased proinflammatory markers in the hypothalamus, also in the C-IF group. Both groups HFru-IF and C-IF, showed alterations in the leptin signaling pathway (Leptin, OBRb, and SOCS3), mainly in the HFru-IF group, suggesting leptin resistance. NPY and POMC neuropeptides labeled the neurons of the hypothalamus by immunofluorescence, corroborating qualitatively other quantitative findings of the study. In conclusion, current results are convincing in demonstrating the IF effect on central regulation of food intake control, as shown by NPY and POMC neuropeptide expressions, resulting in a lower weight gain. Besides, IF improves glycemia, lipid metabolism, and consequently insulin and leptin resistance. However, there is increased expression of inflammatory markers in mouse hypothalamus challenged by the HF and HFru diets, which in the long term may induce adverse effects.