Saturated and unsaturated fat induce hepatic insulin resistance independently of TLR-4 signaling and ceramide synthesis in vivo.
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ABSTRACT:
SUBMITTER: Galbo T
PROVIDER: S-EPMC3732992 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Both high sugar and fat diets can induce prosteatotic genes, leading to obesity and obesity-associated diseases, including hepatic steatosis. Unsaturated fat/fatty acid (USFA) reduces high sugar-induced hepatic steatosis by inhibiting the induced prosteatotic genes. In contrast, it is still unclear how USFA ameliorates saturated fat/fatty acid (SFA)-induced hepatic steatosis. As sugar and fat have different transport and metabolic pathways, we hypothesized that USFA suppressed SFA-induced hepatic steatosis via a different set of prosteatotic genes. To test this, we implemented high SFA vs USFA diets and a control diet in C57BL/6 mice for 16 weeks. Severe hepatic steatosis was induced in mice fed the SFA diet. Among a nearly complete set of prosteatotic genes, only the stearoyl-coenzyme a desaturase 1 (Scd1), cluster of differentiation 36 (Cd36), and peroxisome proliferator-activated receptor γ (Pparγ) genes that were differentially expressed in the liver could contribute to SFA-induced steatosis or the alleviative effect of USFA. That is, the SFA diet induced the expression of Cd36 and Pparγ but not Scd1, and the USFA diet suppressed Scd1 expression and the induction of Cd36 and Pparγ. These findings were mainly recapitulated in cultured hepatocytes. The essential roles of SCD1 and CD36 were confirmed by the observation that the suppression of SCD1 and CD36 with small interfering RNA or drug treatment ameliorated SFA-induced lipid accumulation in hepatocytes. We thus concluded that SCD1, CD36, and PPARγ were essential to the suppression of SFA-induced hepatic steatosis by main dietary USFA, which may provide different therapeutic targets for reducing high-fat vs sugar-induced hepatic steatosis.
| S-EPMC5520982 | biostudies-literature
Project description:BackgroundPartial hepatectomy is a preferred treatment option for many patients with hepatocellular carcinoma however, pre-existing pathological abnormalities originating from hepatic steatosis can alter the decision to perform surgery or postoperative outcomes as a consequence of the impact steatosis has on liver regeneration.AimThe aim of this study was to investigate the role of a saturated or unsaturated high fat diet-mediated steatosis on liver regeneration following partial hepatectomy.MethodsMice were fed a low-fat control diet (CD, 13% fat), lard-based unsaturated (LD, 60% fat) or milk-based saturated high fat diet (MD, 60% fat) for 16 weeks at which time partial hepatectomy (approx. 70% resection) was performed. At days-2 and 7 post hepatectomy, one hour prior to euthanization, mice were injected with 5-bromo-2'-deoxyuridine in order to monitor hepatic regeneration. Serum was collected and assessed for levels of ALT and AST. Resected and regenerated liver tissue were examined for inflammation-indicative markers employing RT-PCR, Western blots, and histological methods.ResultsMice fed LD or MD exhibited higher NAFLD scores, increased expression of inflammatory cytokines, neutrophil infiltration, macrophage accumulation, increased apoptosis, and elevated levels of serum ALT and AST activities, a decrease in the number of BrdU-incorporated-hepatocytes in the regenerated livers compared to the mice fed CD. Mice fed MD showed significantly lower percent of BrdU-incorporated hepatocytes and a higher trend of inflammation compared to the mice fed LD.ConclusionA diet rich in saturated or unsaturated fat results in NASH with decreased hepatic regeneration however unsaturated fat diet cause lower inflammation and higher regeneration than the saturated fat diet following partial hepatectomy in mice.
| S-EPMC10174548 | biostudies-literature
Project description:Aim Non-alcoholic fatty liver disease (NAFLD) is an insulin resistance disease that can progress to cirrhosis and liver failure. We hypothesized that in NAFLD, insulin resistance dysregulates lipid metabolism, increasing production of cytotoxic lipids including ceramides, which exacerbate hepatic insulin resistance and injury.Methods Long Evans rats were pair-fed low (LFD) or high (HFD) fat diets for 8 weeks. Livers were used to measure lipids, gene expression, insulin receptor binding, integrity of insulin signaling, and pro-inflammatory cytokines. In vitro experiments characterized effects of ceramides on Huh7 cell viability, mitochondrial function, and insulin signaling.Results High fat diet feeding caused NAFLD with peripheral and hepatic insulin resistance, increased hepatic expression of pro-ceramide genes, sphingomyelinase activity, and lipid peroxidation, and increased serum ceramide. Ceramide treatment impaired Huh7 cell viability, mitochondrial function, and insulin signaling.Conclusions Increased hepatic ceramide generation and release may mediate both hepatic and peripheral insulin resistance in NAFLD.
| S-EPMC4096625 | biostudies-literature
Project description:ObjectiveNonalcoholic fatty liver disease (i.e., increased intrahepatic triglyceride [IHTG] content), predisposes to type 2 diabetes and cardiovascular disease. Adipose tissue lipolysis and hepatic de novo lipogenesis (DNL) are the main pathways contributing to IHTG. We hypothesized that dietary macronutrient composition influences the pathways, mediators, and magnitude of weight gain-induced changes in IHTG.Research design and methodsWe overfed 38 overweight subjects (age 48 ± 2 years, BMI 31 ± 1 kg/m2, liver fat 4.7 ± 0.9%) 1,000 extra kcal/day of saturated (SAT) or unsaturated (UNSAT) fat or simple sugars (CARB) for 3 weeks. We measured IHTG (1H-MRS), pathways contributing to IHTG (lipolysis ([2H5]glycerol) and DNL (2H2O) basally and during euglycemic hyperinsulinemia), insulin resistance, endotoxemia, plasma ceramides, and adipose tissue gene expression at 0 and 3 weeks.ResultsOverfeeding SAT increased IHTG more (+55%) than UNSAT (+15%, P < 0.05). CARB increased IHTG (+33%) by stimulating DNL (+98%). SAT significantly increased while UNSAT decreased lipolysis. SAT induced insulin resistance and endotoxemia and significantly increased multiple plasma ceramides. The diets had distinct effects on adipose tissue gene expression.ConclusionsMacronutrient composition of excess energy influences pathways of IHTG: CARB increases DNL, while SAT increases and UNSAT decreases lipolysis. SAT induced the greatest increase in IHTG, insulin resistance, and harmful ceramides. Decreased intakes of SAT could be beneficial in reducing IHTG and the associated risk of diabetes.
| S-EPMC7082640 | biostudies-literature
Project description:BackgroundFatty liver disease is a common metabolic abnormality in adolescents with obesity but remains understudied in early childhood.ObjectivesTo describe hepatic fat deposition in prepubertal children and examine cross-sectional associations with metabolic markers and body composition.MethodsData were from 286 children ages 4 to 8 years old in the Healthy Start Study, a longitudinal prebirth cohort in Colorado (USA). Assessments included magnetic resonance imaging to quantify hepatic and abdominal fats, fasting blood draws to measure metabolic markers, and air displacement plethysmography to measure body composition (fat mass and fat-free mass).ResultsThe median (interquartile range) for hepatic fat was 1.65% (1.24%, 2.11%). Log-transformed hepatic fat was higher in Hispanic [mean (95% CI): 0.63 (0.52, 0.74)] vs non-Hispanic white children [0.46 (0.38, 0.53), P = 0.01] and children with overweight/obesity [0.64 (0.49, 0.79)] vs normal-weight [0.47 (0.40, 0.53), P = 0.02]. Higher log-hepatic fat was associated with higher insulin [β (95% CI): 1.47 (0.61, 2.33) uIU/mL, P = 0.001] and estimated insulin resistance (homeostatic model assessment) [0.40 (0.20, 0.60), P < 0.001] in the full sample and glucose [5.53 (2.84, 8.21) mg/dL, P < 0.001] and triglycerides [10.92 (2.92,18.91) mg/dL, P = 0.008] in boys, in linear regression models adjusted for sociodemographics, maternal/perinatal confounders, and percentage body fat. Log-hepatic fat was also associated with abdominal subcutaneous adipose tissue [SAT; 7.37 (1.12,13.60) mm2, P = 0.02] in unadjusted models, but this was attenuated and insignificant after adjusting for confounders.ConclusionsWhile hepatic fat was low in children 4 to 8 years old, it was independently associated with estimated insulin resistance and exhibited sex-specific associations with glucose and triglycerides, suggesting hepatic fat may be an early indicator of metabolic dysfunction in youth.
| S-EPMC8530740 | biostudies-literature
Project description:Lipid-induced insulin resistance is associated with intracellular accumulation of inhibitory intermediates depending on the prevalent fatty acid (FA) species. In cultured myotubes, ceramide and phosphatidic acid (PA) mediate the effects of the saturated FA palmitate and the unsaturated FA linoleate, respectively. We hypothesized that myriocin (MYR), an inhibitor of de novo ceramide synthesis, would protect against glucose intolerance in saturated fat-fed mice, while lisofylline (LSF), a functional inhibitor of PA synthesis, would protect unsaturated fat-fed mice. Mice were fed diets enriched in saturated fat, n-6 polyunsaturated fat, or chow for 6 wk. Saline, LSF (25 mg/kg x d), or MYR (0.3 mg/kg x d) were administered by mini-pumps in the final 4 wk. Glucose homeostasis was examined by glucose tolerance test. Muscle ceramide and PA were analyzed by mass spectrometry. Expression of LASS isoforms (ceramide synthases) was evaluated by immunoblotting. Both saturated and polyunsaturated fat diets increased muscle ceramide and induced glucose intolerance. MYR and LSF reduced ceramide levels in saturated and unsaturated fat-fed mice. Both inhibitors also improved glucose tolerance in unsaturated fat-fed mice, but only LSF was effective in saturated fat-fed mice. The discrepancy between ceramide and glucose tolerance suggests these improvements may not be related directly to changes in muscle ceramide and may involve other insulin-responsive tissues. Changes in the expression of LASS1 were, however, inversely correlated with alterations in glucose tolerance. The demonstration that LSF can ameliorate glucose intolerance in vivo independent of the dietary FA type indicates it may be a novel intervention for the treatment of insulin resistance.
| S-EPMC2940499 | biostudies-literature
Project description:The molecular biology behind hepatic steatosis is unknown. This analysis was done as part of an experiment to understand the role changes in the epigenome have on disease progression. It was done in conjunction with DNA immunoprecipitation sequencing to look at how DNA cytosine species are changed in the context of induction of gene expression.
2017-05-31 | E-MTAB-5520 | biostudies-arrayexpress
Project description:ObjectiveWe recently showed that measurement of the susceptibility of LDL (low-density lipoprotein) to aggregation is an independent predictor of cardiovascular events. We now wished to compare effects of overfeeding different dietary macronutrients on LDL aggregation, proteoglycan-binding of plasma lipoproteins, and on the concentration of oxidized LDL in plasma, 3 in vitro parameters consistent with increased atherogenicity.Approach and resultsThe participants (36 subjects; age, 48+/-10 years; body mass index, 30.9+/-6.2 kg/m2) were randomized to consume an extra 1000 kcal/day of either unsaturated fat, saturated fat, or simple sugars (CARB) for 3 weeks. We measured plasma proatherogenic properties (susceptibility of LDL to aggregation, proteoglycan-binding, oxidized LDL) and concentrations and composition of plasma lipoproteins using nuclear magnetic resonance spectroscopy, and in LDL using liquid chromatography mass spectrometry, before and after the overfeeding diets. LDL aggregation increased in the saturated fat but not the other groups. This change was associated with increased sphingolipid and saturated triacylglycerols in LDL and in plasma and reduction of clusterin on LDL particles. Proteoglycan binding of plasma lipoproteins decreased in the unsaturated fat group relative to the baseline diet. Lipoprotein properties remained unchanged in the CARB group.ConclusionsThe type of fat during 3 weeks of overfeeding is an important determinant of the characteristics and functional properties of plasma lipoproteins in humans.
| S-EPMC8545249 | biostudies-literature
Project description:Sensing of long-chain fatty acids (LCFA) in the hypothalamus modulates energy balance, and its disruption leads to obesity. To date, the effects of saturated or unsaturated LCFA on hypothalamic-brown adipose tissue (BAT) axis and the underlying mechanisms have remained largely unclear. Our aim was to characterize the main molecular pathways involved in the hypothalamic regulation of BAT thermogenesis in response to LCFA with different lengths and degrees of saturation. One-week administration of high-fat diet enriched in monounsaturated FA led to higher BAT thermogenesis compared to a saturated FA-enriched diet. Intracerebroventricular infusion of oleic and linoleic acids upregulated thermogenesis markers and temperature in brown fat of mice, and triggered neuronal activation of paraventricular (PaV), ventromedial (VMH) and arcuate (ARC) hypothalamic nuclei, which was not found with saturated FAs. The neuron-specific protein carnitine palmitoyltransferase 1-C (CPT1C) was a crucial effector of oleic acid since the FA action was blunted in CPT1C-KO mice. Moreover, changes in the AMPK/ACC/malonyl-CoA pathway and fatty acid synthase expression were evoked by oleic acid. Altogether, central infusion of unsaturated but not saturated LCFA increases BAT thermogenesis through CPT1C-mediated sensing of FA metabolism shift, which in turn drive melanocortin system activation. These findings add new insight into neuronal circuitries activated by LCFA to drive thermogenesis.
| S-EPMC9866012 | biostudies-literature
Project description:One hundred and fifty-two nursery pigs (PIC, Hendersonville, TN) were randomly assigned to mix sex pens and one of six dietary treatments in a 3 × 2 factorial. Diets included no added fat, 3% added choice white grease, or 3% added soy oil with either a supplemented vitamin A (for a total of 11,640 IU vitamin A/kg, Rovimix A 1000, DSM, Parsippany, NJ, US) or beta-carotene (for a total of 8,708 IU vitamin A/kg equivalent, Rovimix β-Carotene 10%, DSM). Pigs were given a 3-d adaptation period upon arrival. Pigs were weighed at the start of the study and at the end of each phase. A blood sample was taken from one pig per pen at the start and end of the study. Tissues were collected from eight pigs at the start of the study and six pigs per treatment at the end of the study. Data were analyzed via the GLIMMIX procedure in SAS 9.4 (SAS Inst., Cary, NC). Pen was the experimental unit, and repeated measures were used for growth performance and blood parameters. There was no fat by supplement interaction (P > 0.05) on body weight (BW), but there was a tendency (P = 0.054) for heavier BWs when soy oil was added to diets. There was no difference (P > 0.05) in average daily feed intake or average daily gain (ADG). There was an improved gain:feed (P = 0.02) when pigs were fed choice white grease over no added fat. There were time differences (P < 0.05) for plasma vitamins A (retinol), D (25 hydroxy vitamin D3), and E (alpha-tocopherol). Vitamin A and D values were higher at the end of the study, whereas vitamin E values were lower at the end of the study. The choice white grease diets had the highest (P < 0.05) plasma vitamins D and E (6.74 ng/mL and 2.87 ppm, respectively). Pigs supplemented with vitamin A had higher (P < 0.05) hepatic vitamin A than pigs supplemented with beta-carotene (19.9 vs. 15.6 ppm, respectively). There were no differences (P < 0.05) between immunoglobulins G and M or mRNA abundance of select genes (retinol binding protein 2, alcohol dehydrogenase class 1, lecithin retinol acyltransferase phosphatidylcholine-retinol O-acyltransferase, and beta-carotene oxygenase 1). In conclusion, fat inclusion level and type, with either vitamin A or beta-carotene supplementation, did not affect the overall nursery pig growth performance. The addition of fat resulted in an increase in ADG and BW. Diets with choice white grease had the highest plasma vitamins D and E, and supplemental vitamin A increased hepatic vitamin A.
| S-EPMC10414355 | biostudies-literature