High Saturated Fat Diet Research Articles

Abstract P3035: Role of T Cells in Sex Differences in Blood Pressure Elevation and Adipose Tissue Expansion Following Chronic High Fat Diet Feeding in Dahl Rats

Diets high in saturated fats are increasingly linked to the development of hypertension, yet the mechanisms by which high saturated fat diet (HFD) increases blood pressure remain unclear. Although young women are typically protected from hypertension relative to age-matched men, recent studies suggest that the cardiovascular protection in young women is compromised by chronic consumption of a HFD. We hypothesize that chronic HFD treatment causes a greater increase in blood pressure in females via sex-specific activation and recruitment of T cells and adipocyte expansion. Male and female Dahl rats (n=4-5) were placed on HFD at 8 wks of age. After 4 wks of HFD, blood pressure (BP) significantly increased in male and female Dahl rats to a comparable degree. Although BP continued to increase over the course of 10 wks of HFD treatment, female rats have a greater increases in BP (~40 mmHg increase in BP) after 10 weeks of HFD vs. males (~20 mmHg increase in BP). Fat pad weight and adipose tissue expansion increased in WT rats of both sexes following 10 wks of HFD treatment, yet females exhibited greater increases in fat pad weight and adipose tissue expansion vs. males. To determine whether T cells contributes to sex differences in BP elevation in Dahl rats fed HFD, we utilized Dahl rats lacking CD247 which encodes the T cell receptor CD3 chain that is required for T cell signaling. 10 wks of HF feeding did not change BP in either sex of Dahl CD247 KO rats. There were attenuated increases in fat pad weight and adipocyte expansion in Dahl CD247 KO rats and females exhibited more pronounced attenuations than males. Flow cytometric analysis revealed that HFD decreased Tregs and increased Th17 cells in both sexes of Dahl WT rats and females on HFD had the most pro-inflammatory T cell profile indicted by the Th17 cells:Tregs ratio. Our data suggest that greater adipocyte expansion with a HFD feeding in female Dahl rats vs. male might result in greater recruitment and activation of pro-inflammatory T cells and larger increases in BP.

Dietary Fatty Acid Saturation Modulates Sphingosine-1-Phosphate-Mediated Vascular Function

Sphingolipids, modified by dietary fatty acids, are integral components of plasma membrane and caveolae that are also vasoactive compounds. We hypothesized that dietary fatty acid saturation affects vasoconstriction to sphingosine-1-phosphate (S1P) through caveolar regulation of rho kinase. Wild type (WT) and caveolin-1-deficient (cav-1 KO) mice which lack vascular caveolae were fed a low-fat diet (LF), 60% high-saturated fat diet (lard, HF), or 60% fat diet with equal amounts of lard and n-3 polyunsaturated menhaden oil (MO). Weight gain of WT on HF and MO diets was similar while markedly blunted in cav-1 KO. Neither high-fat diet affected the expression of cav-1, rho, or rho kinase in arteries from WT. In cav-1 KO, MO increased the vascular expression of rho but had no effect on rho kinase. HF had no effect on rho or rho kinase expression in cav-1 KO. S1P produced a concentration-dependent constriction of gracilis arteries from WT on LF that was reduced with HF and restored to normal with MO. Constriction to S1P was reduced in cav-1 KO and no longer affected by a high-saturated fat diet. Inhibition of rho kinase which reduced constriction to PE independent of diet in arteries from WT and cav-1 KO only reduced constriction to S1P in arteries from WT fed MO. The data suggest that dietary fatty acids modify vascular responses to S1P by a caveolar-dependent mechanism which is enhanced by dietary n-3 polyunsaturated fats.

A Cholecystokinin Receptor Antagonist Halts Nonalcoholic Steatohepatitis and Prevents Hepatocellular Carcinoma

Background and AimsNonalcoholic steatohepatitis (NASH) is a common inflammatory liver condition that may lead to cirrhosis and hepatocellular carcinoma (HCC). Risk factors for NASH include a saturated fat diet, altered lipid metabolism, and genetic and epigenetic factors, including microRNAs. Serum levels of cholecystokinin (CCK) are elevated in mice and humans that consume a high-saturated fat diet. CCK receptors (CCK-Rs) have been reported on fibroblasts which when activated can induce fibrosis; however, their role in hepatic fibrosis remains unknown. We hypothesized that elevated levels of CCK acting on the CCK-Rs play a role in the development of NASH and in NASH-associated HCC.MethodsWe performed a NASH Prevention study and Reversal study in mice fed a saturated fat 75% choline-deficient–ethionine-supplemented (CDE) diet for 12 or 18 weeks. In each study, half of the mice received untreated drinking water, while the other half received water supplemented with the CCK-R antagonist proglumide. CCK-R expression was evaluated in mouse liver and murine HCC cells.ResultsCCK receptor antagonist treatment not only prevented NASH but also reversed hepatic inflammation, fibrosis, and steatosis and normalized hepatic transaminases after NASH was established. Thirty-five percent of the mice on the CDE diet developed HCC compared with none in the proglumide-treated group. We found that CCK-BR expression was markedly upregulated in mouse CDE liver and HCC cells compared with normal hepatic parenchymal cells, and this expression was epigenetically regulated by microRNA-148a.ConclusionThese results support the novel role of CCK receptors in the pathogenesis of NASH and HCC.

Host-microbiome interactions in response to a high-saturated fat diet and fish-oil supplementation in zebrafish adult

Abstract Diet is one of the main factors affecting host’s health. The aim of this work was to study the interaction among nutrition, microbiota and host, using zebrafish adults as animal model. Thus, the effects of a high-saturated-fat diet, and its supplementation with a commercial fish-oil on fish lipid profile, intestinal microbiota and blood glucose were evaluated. The dietary saturated fat changed the fish lipid profile, microbial community composition, and its metabolism. Saturated fatty acids levels were higher in fish fed the high-saturated-fat diet, which correlated with an increased in Pseudomonas. Otherwise, the commercial fish-oil intake ameliorated the effect of the fat on the lipid profile, lowering saturated fatty acid levels while increasing polyunsaturated fatty acids. It also contributed to limit the growth of Pseudomonas on intestinal microbial community. Furthermore, blood glucose diminished in animals fed fish-oil supplemented diet. This suggests that fish-oil may mitigate the effect of the high-saturated-fat-diet.

High Saturated and Unsaturated Fat Diets Yield Different Disease Phenotypes in Mice

Excessive consumption of unsaturated or saturated fatty acids have adverse effects on certain health parameters, namely increased risk of obesity, diabetes, and cardiovascular disease. Specifically, saturated fats are linked to increased cardiovascular risk while unsaturated fats are suggested to protect against cardiovascular disease. Our previous work suggested that various high fat diets have differential effects on cardiac hypertrophy and function. However, it was not clear whether a high saturated fat diet (HSFD) or high unsaturated fat diet (HUFD) could elicit different disease phenotypes. Therefore, the purpose of this study was to evaluate the effects of HSFD or HUFD on the development of obesity, diabetes, and cardiac lipotoxicity in mice. Male, C57BL/6J mice received normal chow (CON, n=12), HSFD (n=15) or HUFD (n=15) for 12 weeks. Body weight and food intake were measured weekly. After 12 weeks, the adipose tissue and heart were removed and weighed. Glucose, fatty acids, and cholesterol were analyzed in serum using biochemical assays. Cardiac triglycerides (TG) were measured in heart tissue extracts. Both HSFD and HUFD significantly increased body weight above CON. Interestingly, body weight increased by ~63% in the HUFD while the HSFD increased ~41% (P<0.05). Adipose tissue mass was increased 5‐fold in both HFD groups and was ~10% greater in the HUFD. Surprisingly, caloric intake was higher in the HSFD (15.3±0.8) compared to HUFD (12.8±0.1) and CON (11.9±0.7). Serum cholesterol levels were elevated in both HSFD and HUFD. Blood glucose was significantly increased only in the HUFD while serum fatty acids were increased only in the HSFD. Cardiac hypertrophy, assessed by the heart weight to tibia length ratio, was increased in the HSFD but not HUFD group. Cardiac TGs were ~25% higher in HSFD but <10% in HUFD compared to CON. These data show that excess consumption of saturated or unsaturated fats increased body weight and adiposity in mice. However, high consumption of unsaturated fatty acids resulted in a pronounced increase in body weight, body fat, and hyperglycemia, consistent with an obese and diabetic phenotype. Conversely, high consumption of saturated fatty acids caused elevated serum lipids, cardiac hypertrophy, and cardiac lipid accumulation, consistent with cardiac lipotoxicity. In conclusion, the fatty acid composition of diets may be critical in the development of disease phenotypes resulting from high fat feeding in mice.Support or Funding InformationThis work was supported by funding from the American Heart Association and Ursinus College.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Effects of a Low Fat Diet versus a High Fat Diet on Lymphoid Cell Infiltration in a Mouse Model of Oral Cancer

IntroductionRisk factors for oral cancer include tobacco use, male sex, and possibly dietary fat. Exposure to 4‐nitroquinoline 1‐oxide (4NQO) in the drinking water causes oral cancer in mice and models the effects of tobacco use. This study was undertaken to investigate the effects of a high saturated fat (HF) or low fat (LF) diet and sex on presence of lymphoid cells in cancerous tongues. We hypothesized that inflammation, characterized by the increased presence of lymphoid cells, would accompany development of tumor lesions and that sex and diet would affect the levels of inflammation.MethodsMale and female C57Bl/6 mice (36 each gender), 5 weeks old, were divided into a low fat (10kcal% fat; LF) or HF (60 kcal% fat) diet. Within each dietary group, mice were randomly assigned to one of 3 water treatment groups for 17 weeks: water alone (control); propylene glycol in water (1.25%; PG‐H2O); or 4NQO in PG‐H2O (50 mg/ml; 4NQO). After 17 weeks, all mice were given water alone for 6 more weeks. Tongues harvested from the euthanized animals were fixed in formalin and processed for histological examination. T cells (CD3+ cells), macrophages (CD68+ cells), and neutrophils (Ly6+ cells) were detected by immunohistochemistry, counted, and normalized to tissue area. Analysis was done using GraphPad Prism 7.0. All animal work was in compliance with the regulations of IACUC at Midwestern University, Downers Grove, IL.ResultsOral cancer developed in all mice exposed to 4NQO and was absent in all controls. All three lymphoid cell types were significantly higher (p<0.05) in the 4NQO mice versus the control mice: CD3+ (11.2 vs 0.9 cells/mm2), CD68+ (3.6 vs 1.5 cells/mm2), and Ly6+ (9.4 vs 0.38 cells/mm2). Among the 4NQO treated mice, there were no significant differences between males and females, or between HF and LF mice for T cells or macrophages. 4NQO treated males had a significantly higher numbers of neutrophils than females (12 vs 6.6 cells/mm2). LF diet increased the levels of neutrophils in both males and females (15 and 7.7 cells/mm2 respectively) when compared to the HF diet in both males and females (9.3 and 5.3 cells/mm2 respectively); however, this trend was not statistically significant. We speculate that the higher carbohydrate content of the LF diet may support increased anaerobic glycolytic metabolism via the Warburg effect.ConclusionDevelopment of 4NQO‐induced oral cancer was accompanied by inflammatory responses as manifested by the presence of T cells, macrophages, and neutrophils. Neutrophils were the only cell type affected by sex and possibly by the content of dietary fat.Support or Funding InformationThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Expression of Folate Transport Proteins in a Mouse Model of 4NQO‐Induced Oral Cancer

IntroductionHead and neck cancer is the sixth most common cancer worldwide. Risk factors include tobacco exposure, alcohol use, male sex, and a poor diet. Administration of 4‐nitroquinoline‐1‐oxide (4NQO) in drinking water causes oral cancer in mice, and mimics the effects of tobacco use. Folate is essential for nucleotide biosynthesis as well as epigenetic regulation. Folate is imported by folate receptors (FR), proton‐coupled folate transporters (PCFT), and the reduced folate carrier (RFC). This study aimed to investigate the effects of a high saturated fat (HF) or low fat (LF) diet, sex, and 4NQO treatment on expression of folate transport proteins in mice tongues. We hypothesized that there would be a decreased expression of these proteins in the HNSCC tongue samples compared to the control tongue samples.Materials and MethodsFive week old mice (C57BI/6, 36 per sex) were provided either a low saturated fat diet (10 kcal% fat; LF) or a high fat diet (60 kcal% fat, HF). After one week, mice were then randomly assigned to 17 weeks on one of three water treatment groups: water alone (control); propylene glycol in water (1.25%, PG‐water); or 4NQO in PG‐water (50 mg/ml; 4NQO). After 17 weeks, the mice were provided water alone for six more weeks but maintained on their diet. Tongues from euthanized animals were fixed in formalin and processed for histological examination. Immunohistochemistry was performed to detect the expression of FR, PCFT, and RFC in these samples. Slides were visually graded, and the total score for the expression of each protein was acquired by adding the intensity grade (0–3) and distribution grade (0–3). Statistical analysis was performed using Graphpad Prism 7.0. All animal work was in compliance with the Institutional Animal Care and Use Committee at Midwestern University, Downers Grove, IL.ResultsCompared to the control tongues, there was decreased expression of all three folate transport proteins in tumors (p<0.001). The total score (intensity + distribution) in oral cancer versus control tissue for FR, RFC, and PCFT, respectively were: 3.21 ± 0.10 vs 4.48 + 0.14; 4.38 ± 0.11 vs 5.13 ± 0.10; and 4.22 ± 0.11 vs 5.65 ± 0.69. All slides displayed a 100% distribution rate of FR, PCFT, and RFC in the epithelium. There were no significant differences in folate transport protein expression in males versus females. In the 4NQO tongues, a statistically significant decrease in FR expression was observed between the HF diet group and the LF group (3.97 ± 0.20 vs 3.05 ± 0.10, p <0.0002). No differences were observed in the expression of RFC and PCFT proteins with regards to diet or sex.ConclusionWe measured decreased expression in all three folate transport proteins in oral cancers when compared to normal tongue epithelium. We speculate that mutations leading to decreased folate import can promote carcinogenesis through epigenetic mechanisms.Support or Funding InformationThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Can Carob-Fruit-Extract-Enriched Meat Improve the Lipoprotein Profile, VLDL-Oxidation, and LDL Receptor Levels Induced by an Atherogenic Diet in STZ-NAD-Diabetic Rats?

Carob fruit extract (CFE) has shown remarkable in vitro antioxidant properties and reduces postprandial hyperglycemia and hyperlipidemia in healthy animals. Development of functional meat products that contain bioactive components are presented as a great nutritional strategy. Until now, the effect of the consumption of restructured meat enriched with CFE in a murine model of diabetes has not been investigated. The objective of this study was to evaluate the effect on glycemia, lipemia, lipoprotein profile, Ldlr, arylesterase (AE), and very low-density lipoproteins (VLDL) and liver oxidation in streptozotocin-nicotinamide (STZ-NAD) growing Wistar diabetic rats fed restructured meat in the frame of a high cholesterol/high saturated-fat diet. In the present study, three groups (D, ED and DE) were fed cholesterol-enriched (1.4% cholesterol and 0.2% cholic acid) and high saturated-fat diets (50% of total energy from fats and 20.4% from saturated fatty acids). Rats were subjected to a STZ-NAD administration at the 3rd week. Group D did not receive CFE, while ED and DE rat groups received CFE before and after the diabetic induction, respectively. After eight weeks, D rats showed hyperglycemia and hypercholesterolemia, an increased amount cholesterol-enriched VLDL (β-VLDL), IDL and LDL particles and triglyceride-enriched HDL. ED and DE partially blocked the hypercholesterolemic induction with respect to D group (p < 0.001) and improved glycemia, cholesterol levels, lipoprotein profile, Ldlr, plasma AE activity and liver oxidation (p < 0.001). Fecal fat, moisture and excretion were higher while dietary digestibility was lower in ED and DE vs. D counterparts (p < 0.0014). In conclusion, CFE-enriched meat shows, for the first time, hypoglycemic and hypolipidemic effects in STZ-NAD animals fed high cholesterol/high saturated-fat diets. Likewise, it manages to reverse possible diabetes lipoprotein alterations if CFE-enriched meat is consumed before pathology development or improves said modifications if Type 2 Diabetes Mellitus is already established.

Uloga kanabinoidnih CB1 receptora u razvoju oksidativnog/nitrozativnog stresa u toku nealkoholne masne bolesti jetre kod miševa

Introduction: Non-Alcoholic Fatty Liver Disease (NAFLD) is hepatic manifestation of metabolic syndrome. It represents a spectrum of diseases ranging from steatosis, non-alcoholic steatohepatitis (NASH), that may progress to fibrosis, cirrhosis and eventually hepatocellular carcinoma. Aim: the aim of the study was to investigate the influence of CB 1 cannabinoid receptor blockade on the intensity of oxidative/nitrosative stress in mice liver with NAFLD. Therefore, we used rimonabant, selective CB 1 antagonist. Material and Methods: Male mice C57BL/6 (n = 28) were divided into following groups: 1) Control group-fed with control chow diet 20 weeks (C group; n = 7), 2) Group fed with high saturated fat diet 20 weeks (HF group; n = 7), 3) Group fed with standard chow diet and treated with rimonabant after 18 weeks (R group; n = 7), 4) Group fed with high saturated fat diet and treated with rimonabant after 18 weeks (HFR group; n = 7). The activity of liver tran-saminases was measured in serum. The concentrations of malondialdehyde (MDA), nitrites and nitrates (NO x), and the activity of superoxide dismutase (SOD), copper/zinc superoxide dismutase (Cu/ZnSOD) and manganese superoxide dismutase (MnSOD) were measured in the liver. Results: Rimonabant induced decrease in transaminase activity in R group compared to control , as well as in HFR group compared to HF group (p < 0.01, respectively). Concentrations of MDA and NO x were lower in HFR compared to HF group (p < 0.01). We found decrease in SOD, Cu/ZnSOD and MnSOD activities in HFR group compared to HF group (p < 0.01). Conclusion: According to the results of this study, it can be concluded that blockade of CB 1 receptors causes useful effects in the treatment of NAFLD. Rimonabant reduced hepatocellu-lar injury, which was proved by decreased transaminase activities. The reduction of oxidative/ nitrosative stress and lipid peroxidation may also contribute to the protective effects of rimonabant, which has been shown as decrease in MDA and NOx concentration.

High-Saturated Fat High-Sugar Diet Accelerates Left-Ventricular Dysfunction Faster than High-Saturated Fat Diet Alone via Increasing Oxidative Stress and Apoptosis in Obese-Insulin Resistant Rats.

It has been hypothesized that a high-saturated-fat, high-sugar diet (HFHS) causes worse cardiometabolic dysfunction than a high-saturated-fat diet (HFD) due to severe mitochondrial dysfunction, oxidative stress, and apoptosis in obese insulin-resistant rats. Rats are divided into three groups to receive normal diet (ND), HFD, or HFHS for 24 weeks. Cardiometabolic parameters are determined at baseline and every 4 weeks until the end of the feeding protocol. At week 24, hearts are removed to determine mitochondrial function and dynamics, apoptosis, and insulin signaling. HFD and HFHS rats develop obese insulin-resistance at week 8. However, fasting plasma glucose level is increased only in HFHS rats. Myocardial insulin signaling is markedly impaired in HFHS rats compared to other groups. Cardiac autonomic imbalance is observed in both HFD and HFHS rats beginning at week 8. However, cardiac dysfunction is observed earlier (week 8) in HFHS rats, and later at week 12 in HFD rats. Moreover, cardiac and mitochondrial oxidative stress levels, and apoptosis are greater in HFHS rats than HFD rats. Both HFD and HFHS cause cardiometabolic dysfunction. HFHS causes more severe metabolic disturbance, oxidative stress, and apoptosis than HFD, which leads to an accelerated LV dysfunction in HFHS rats.

Liver tumorigenesis is promoted by a high saturated fat diet specifically in male mice and is associated with hepatic expression of the proto-oncogene Agap2 and enrichment of the intestinal microbiome with Coprococcus.

Liver cancer results in a high degree of mortality, especially among men. As fatty liver disease is a risk factor for development of hepatocellular carcinoma, we investigated the role of dietary fat type in tumor promotion by high-fat diets in mice after initiation with the chemical carcinogen diethyl nitrosamine. Tumor incidence and multiplicity were significantly greater in males than those in females. In males, fat type had complex effects on tumorigenesis. Preneoplastic foci were most prevalent in mice fed a polyunsaturated fat diet enriched in docosahexaenoic acid, whereas carcinomas and large visible liver tumors were significantly greater in mice fed a saturated fat diet made with cocoa butter relative to mice fed mono- or polyunsaturated fats. Different mechanisms thus seemed involved in early and late tumor promotion. The hepatic transcriptome and gut microbiome were assessed for traits associated with tumorigenesis. Hepatic expression of more than 20% of all genes was affected by sex, whereas fat type affected fewer genes. In males, the saturated fat diet induced expression of the proto-oncogene Agap2 and affected the expression of several cytochrome P450 genes, and genes involved in lipid, bile acid and fatty acid metabolism. The gut microbiome had a higher level of genus Akkermansia and a lower level of Firmicutes in females than in males. Males fed saturated fat had an altered microbiome, including an enrichment of the genus Coprococcus. In conclusion, sex and the dietary fat type affect the gut microbiome, the hepatic transcriptome and ultimately hepatic tumor growth.

High-fat diet consumption alters energy metabolism in the mouse hypothalamus.

High-fat diet consumption is known to trigger an inflammatory response in the hypothalamus, which has been characterized by an initial expression of pro-inflammatory genes followed by hypothalamic astrocytosis, microgliosis, and the appearance of neuronal injury markers. The specific effects of high-fat diet on hypothalamic energy metabolism and neurotransmission are however not yet known and have not been investigated before. We used 1H and 13C magnetic resonance spectroscopy (MRS) and immunofluorescence techniques to evaluate in vivo the consequences of high-saturated fat diet administration to mice, and explored the effects on hypothalamic metabolism in three mouse cohorts at different time points for up to 4 months. We found that high-fat diet increases significantly the hypothalamic levels of glucose (P < 0.001), osmolytes (P < 0.001), and neurotransmitters (P < 0.05) from 2 months of diet, and alters the rates of metabolic (P < 0.05) and neurotransmission fluxes (P < 0.001), and the contribution of non-glycolytic substrates to hypothalamic metabolism (P < 0.05) after 10 weeks of high-fat feeding. We report changes that reveal a high-fat diet-induced alteration of hypothalamic metabolism and neurotransmission that is quantifiable by 1H and 13C MRS in vivo, and present the first evidence of the extension of the inflammation pathology to a localized metabolic imbalance.

A chronic LPS-induced low-grade inflammation fails to reproduce in lean mice the impairment of preference for oily solution found in diet-induced obese mice

Diet-induced obesity (DIO) is associated with a decreased oral fat detection in rodents. This alteration has been explained by an impairment of the lipid-mediated signaling in taste bud cells (TBC). However, factors responsible for this defect remain elusive. Diet rich in saturated fatty acids is known to elicit a metabolic inflammation by promoting intestinal permeation to lipopolysaccharides (LPS), Gram-negative bacteria-derived endotoxins. To determine whether a local inflammation of the gustatory tissue might explain the obese-induced impairment of the oro-sensory detection of lipids, mice were subjected to a DIO protocol. Using a combination of behavioral tests, transcriptomic analyses of gustatory papillae and biochemical assays, we have found that i) DIO elicits a pro-inflammatory genic profile in the circumvallate papillae (CVP), known to house the highest density of lingual taste buds, ii) NFkB, a key player of inflammatory process, might play a role in this transcriptomic pattern, iii) plasma LPS levels are negatively correlated with the preference for oily solution, and iv) a chronic infusion of LPS at a level similar to that found in DIO mice is not sufficient to alter the spontaneous preference for fat in lean mice. Taken together these data bring the demonstration that a saturated high fat diet elicits an inflammatory response at the level of peripheral gustatory pathway and a LPS-induced low-grade endotoxemia alone does not explain the change in the preference for dietary lipids observed in DIO mice.

Changes in markers for cardio-metabolic disease risk after only 1-2 weeks of a high saturated fat diet in overweight adults.

PurposeDiets high in saturated fat acids (SFA) have been linked with cardio-metabolic disease risk. The purpose of this study was to determine whether only 1–2 weeks of a high SFA diet could impact disease risk factors in overweight adults who normally eat a relatively low proportion of SFA (i.e., <40% of dietary fat).MethodsTwelve overweight (BMI: 27±1 kg/m2) young adults were studied before and after a 2-week diet that increased the proportion of SFA (<40% to 60% of dietary fat), while maintaining their daily intake of total fat, carbohydrate, protein, and calories. Insulin resistance, blood pressure, plasma markers of liver damage, total plasma cholesterol concentrations, and fatty acid profile within plasma and skeletal muscle lipid pools were assessed before and after the intervention.ResultsTotal plasma cholesterol concentration increased (148±5 vs. 164±8 mg/dl; P<0.05) after only one week, due exclusively to an increase in LDL-cholesterol (78±4 vs. 95±7 mg/dl; P<0.05). After two weeks, plasma aspartate amino transferase (AST) concentration increased (P<0.05) but we found no change in insulin resistance, or resting blood pressure. The diet increase the proportion of SFA in plasma (35±1% vs. 39±2%; P<0.05) and the intramyocellular triglyceride pool (32±1% vs. 37±1%; P<0.05) suggesting the fatty acids in these pools may readily exchange.ConclusionsAlthough blood lipids remain within normal clinical range, increasing saturated fat in diet for only 2 weeks raises plasma markers of cardiovascular risk (LDL-cholesterol) and liver damage (AST). In overweight, but healthy-young adults SFA accumulate in plasma and muscle after only 1–2 weeks of dietary increase.

Prenatal Exposure to a Maternal High Fat Diet Increases Hepatic Cholesterol Accumulation in Intrauterine Growth Restricted Rats in Part Through MicroRNA-122 Inhibition of Cyp7a1.

Intrauterine growth restriction (IUGR) and consumption of a high saturated fat diet (HFD) increase the risk of hypercholesterolemia, a leading cause of morbidity and mortality. The mechanism through which the cumulative impact of IUGR and in utero exposure to a maternal HFD increase cholesterol levels remains unknown. Cholesterol 7α hydroxylase (Cyp7a1) initiates catabolism of cholesterol to bile acids for elimination from the body, and is regulated by microRNA-122 (miR-122). We hypothesized that IUGR rats exposed to a maternal HFD would have increased cholesterol and decreased Cyp7a1 protein levels in juvenile rats, findings which would be normalized by administration of a miR-122 inhibitor. To test our hypothesis we used a rat model of surgically induced IUGR and fed the dams a regular diet or a HFD from prior to conception through lactation. At the time of weaning, IUGR female rats exposed to a maternal HFD had increased hepatic cholesterol, decreased hepatic Cyp7a1 protein and hepatic bile acids, and increased hepatic miR-122 compared to non-IUGR rats exposed to the same HFD. In vivo inhibition of miR-122 increased hepatic Cyp7a1 protein and decreased hepatic cholesterol. Our findings suggest that IUGR combined with a maternal HFD decreased cholesterol catabolism to bile acids, in part, via miR-122 inhibition of Cyp7a1.

Abstract 598: Monounsaturated Fat Reduces Foamy Monocyte Formation and Atherosclerosis Development in Ldlr -/- Mice Compared to Western High Saturated Fat Diet

Monounsaturated fat (MUF)-rich Mediterranean-type diet (MedD) has been reported to improve atherosclerotic outcome in clinical studies, but the underlying mechanism is ill defined. Circulating foamy monocytes (FMs, monocytes with intracellular lipid droplets), which are CD11c + and highly adherent to inflamed endothelium, contribute to atherosclerosis development. In the present study, we investigated the influence of MedD on FM formation and its contribution to atherosclerosis in mice. LDLR -/- mice were fed MedD with high cholesterol (MedD [w/w, 21% total fat from olive oil and nut] containing 2.6% saturated fat and 13.4% MUF; 0.2% cholesterol) or western diet (WD, 21% milkfat-containing 13.3% saturated fat and 5.9% MUF; 0.2% cholesterol), with normal diet (ND) as control. Lesion area of the whole aorta examined by oil red staining at 3 months was significantly reduced in mice on MedD, compared to WD. Although plasma triglyceride levels were lower in mice on MedD than on WD, the free fatty acid profile indicated that MUFs concentration in plasma significantly increased in mice on MedD. Further, FMs from mice on MedD circulated at lower proportions and exhibited lower side scatter (SSC) than WD, indicating less lipid accumulation. Lipid accumulation in FMs from mice on WD accelerated their conversion from CD11c - /CD36 + to CD11c + /CD36 + compared to mice on ND. In contrast, this accelerated conversion did not occur in mice on MedD. Compared to WD, MedD reduced the number of firmly arrested CD11c + monocytes on vascular cell adhesion molecule-1 and E-selectin coated coverslips detected in an ex-vivo shear flow assay. Similarly, fewer CD11c + macrophages were observed in the lesion of aortic sinus in mice on MedD than on WD. In summary, compared to WD high in saturated fat and cholesterol, MedD high in MUF and cholesterol lowered triglyceride levels, inhibited foamy monocyte formation and adhesion, and reduced atherosclerosis in LDLR -/- mice.

High Fat Diet Exacerbates 4NQO‐Induced Liver Pathology in Mice

IntroductionA variety of factors, including use of tobacco, diet, gender, and genetics impact cancer risk. It is well established that administration of 4‐nitroquinonline 1‐oxide (4NQO) in drinking water mimics the effects of tobacco and leads to development of oral carcinoma in mice. The purpose of this study was to determine whether administration of 4NQO induced liver pathology and to examine the effects of gender, and high and low saturated fat diets (HF and LF, respectively) on the liver histopathology. We hypothesized that 4NQO's carcinogenic effects would cause pathological changes in liver and a HF diet would exacerbate this process.Materials and methodsMale and female C57Bl/6 mice (36 each gender), 5 weeks old, were divided into a low fat (10 kcal% fat; LF) or HF (60 kcal% fat) diet. Within each dietary group, mice were randomly assigned to one of 3 water treatment groups for 17 weeks: water alone (control); propylene glycol in water (1.25%; PG‐H2O); or 4NQO in PG‐H2O (50 mg/ml; 4NQO). After 17 weeks, all mice were given water alone for 6 more weeks. Livers harvested from the euthanized animals were weighed, then fixed in formalin and processed for histological examination. In addition, neutrophils and macrophages were detected by immunocytochemistry (Ly6 and CD68 positive cells, respectively) and counted in a standard area in liver sections. T‐tests were used to confirm no difference between water and PG controls, which were then combined for further statistical analysis using GraphPad Prism 7.0.ResultsAdministration of 4NQO resulted in histopathological changes in liver in all treatment groups. Morphological changes in hepatocytes, the presence of lobular and portal lymphoid cell infiltrates, and periportal fibrosis were observed in hematoxylin and eosin‐stained tissues. In addition, HF diet resulted in severe steatosis and liver enlargement (3× higher liver index in HF males versus all other treatment groups) of male but not female controls. Treatment with 4NQO significantly increased the number of neutrophils in liver, when compared to non‐4NQO‐treated control livers in HF males (208 versus 24.7), HF females (100 versus 29.2), and LF females (80 versus 26.7; for all groups, p&lt;0.05). Also, treatment with 4NQO increased the number of macrophages in HF males, when compared to non‐4NQO‐treated males (121 versus 55, p&lt;0.05). In addition, HF diet exacerbated the effect of 4NQO in males, with 121 neutrophils in HF 4NQO‐treated males versus 94.1 neutrophils in LF 4NQO‐treated males (p = 0.05).ConclusionOral administration of 4NQO, which mimics the effects of tobacco, induces histopathological changes in the liver, and those changes are exacerbated by a HF diet, especially in males.Support or Funding InformationWe recognize the Midwestern University Deans of the College of Dental Medicine and the Basic Science Division for their support of this research. Student research was supported by the Office of Research and Sponsored Programs and the Biomedical Sciences Division.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Effects of Dietary Fatty Acids in Pancreatic Beta Cell Metabolism, Implications in Homeostasis.

Fatty acids are involved in several metabolic processes, including the development of metabolic and cardiovascular diseases. In recent years a disease that has received escalated interest is type 2 diabetes (T2D). Many contributing factors including a high-caloric diet rich in dietary saturated fats have been broadly characterized as triggers of T2D. Insulin resistance resulting from a high saturated fat diet leads to alterations in lipid cellular intake and accumulation which generate lipotoxic conditions, a key phenomenon in the metabolism of β-cells. Alternatively, unsaturated fatty acids have been described to show opposite effects in pancreatic β-cells. The purpose of this work is to perform a critical analysis of the complex role of saturated and unsaturated fatty acids in β-cell metabolism. We discuss the diverse effects main dietary fatty acids have upon pancreatic β-cell metabolism as a key factor to maintain homeostasis by focusing in the cellular and molecular mechanisms involved in the development and progression of T2D. For instance, modifications in protein homeostasis as well as the intracellular management of lipid metabolism which are associated with inflammatory pathways. These conditions initiate critical metabolic rearrangements, that in turn have repercussions on insulin β-cell metabolism. This review allows an integral and broad understanding of different functions of fatty acids inside β-cells, being important metabolites for novel therapeutic targets in T2D treatment.

Pathological hypertrophy and cardiac dysfunction are linked to aberrant endogenous unsaturated fatty acid metabolism.

Pathological cardiac hypertrophy leads to derangements in lipid metabolism that may contribute to the development of cardiac dysfunction. Since previous studies, using high saturated fat diets, have yielded inconclusive results, we investigated whether provision of a high-unsaturated fatty acid (HUFA) diet was sufficient to restore impaired lipid metabolism and normalize diastolic dysfunction in the pathologically hypertrophied heart. Male, Wistar rats were subjected to supra-valvar aortic stenosis (SVAS) or sham surgery. After 6 weeks, diastolic dysfunction and pathological hypertrophy was confirmed and both sham and SVAS rats were treated with either normolipidic or HUFA diet. At 18 weeks post-surgery, the HUFA diet failed to normalize decreased E/A ratios or attenuate measures of cardiac hypertrophy in SVAS animals. Enzymatic activity assays and gene expression analysis showed that both normolipidic and HUFA-fed hypertrophied hearts had similar increases in glycolytic enzyme activity and down-regulation of fatty acid oxidation genes. Mass spectrometry analysis revealed depletion of unsaturated fatty acids, primarily linoleate and oleate, within the endogenous lipid pools of normolipidic SVAS hearts. The HUFA diet did not restore linoleate or oleate in the cardiac lipid pools, but did maintain body weight and adipose mass in SVAS animals. Overall, these results suggest that, in addition to decreased fatty acid oxidation, aberrant unsaturated fatty acid metabolism may be a maladaptive signature of the pathologically hypertrophied heart. The HUFA diet is insufficient to reverse metabolic remodeling, diastolic dysfunction, or pathologically hypertrophy, possibly do to preferentially partitioning of unsaturated fatty acids to adipose tissue.

High Dietary Saturated Fat is Associated with a Low Risk of Intracerebral Hemorrhage and Ischemic Stroke in Japanese but not in Non-Japanese: A Review and Meta-Analysis of Prospective Cohort Studies.

Aim: The associations between dietary saturated fatty acids and the risks of stroke subtypes in cohort studies were examined by a meta-analysis of separate ethnic Japanese and non-Japanese cohorts, and causes of their difference were elucidated.Method: Log hazard ratio (HR) with 95% confidence interval (CI) of the highest versus the lowest saturated fat intake from cohort studies were weighed by an inverse variance method to combine HRs.Results: Five studies of intracerebral hemorrhage and 11 studies/comparisons of ischemic stroke were selected. A meta-analysis of intracerebral hemorrhage excluding subarachnoid hemorrhage showed a strong inverse association in Japanese (n = 3, HR = 0.55, 95% CI 0.32–0.94) but not in non-Japanese (n = 2, HR = 0.98, 95% CI 0.62–1.53). A meta-analysis of ischemic stroke showed a mild inverse association in Japanese (n = 4, HR = 0.82, 95% CI 0.71–0.93) but not in non-Japanese (n = 7, HR = 0.93, 95% CI 0.84–1.03). The effect size of saturated fat in reducing the risk of stroke in Japanese was stronger for intracerebral hemorrhage (45% reduction) than for ischemic stroke (18% reduction).Conclusions: In Japanese but not in non-Japanese, a diet high in saturated fat is associated with a low risk of intracerebral hemorrhage and ischemic stroke. This may be due to differences in the range of intake of saturated fat, genetic susceptibility, incidence of lacunar infarction, and/or confounding factors such as dietary proteins. An intervention study targeting Japanese will be required to verify the causality.