Hepatic stearoyl-CoA Desaturase Research Articles

High-Fat Feeding Alters Circulating Triglyceride Composition: Roles of FFA Desaturation and ω-3 Fatty Acid Availability.

Hypertriglyceridemia is a risk factor for type 2 diabetes and cardiovascular disease (CVD). Plasma triglycerides (TGs) are a key factor for assessing the risk of diabetes or CVD. However, previous lipidomics studies have demonstrated that not all TG molecules behave the same way. Individual TGs with different fatty acid compositions are regulated differentially under various conditions. In addition, distinct groups of TGs were identified to be associated with increased diabetes risk (TGs with lower carbon number [C#] and double-bond number [DB#]), or with decreased risk (TGs with higher C# and DB#). In this study, we examined the effects of high-fat feeding in rats on plasma lipid profiles with special attention to TG profiles. Wistar rats were maintained on either a low-fat (control) or high-fat diet (HFD) for 2 weeks. Plasma samples were obtained before and 2.5 h after a meal (n = 10 each) and subjected to lipidomics analyses. High-fat feeding significantly impacted circulating lipid profiles, with the most significant effects observed on TG profile. The effects of an HFD on individual TG species depended on DB# in their fatty acid chains; an HFD increased TGs with low DB#, associated with increased diabetes risk, but decreased TGs with high DB#, associated with decreased risk. These changes in TGs with an HFD were associated with decreased indices of hepatic stearoyl-CoA desaturase (SCD) activity, assessed from hepatic fatty acid profiles. Decreased SCD activity would reduce the conversion of saturated to monounsaturated fatty acids, contributing to the increases in saturated TGs or TGs with low DB#. In addition, an HFD selectively depleted ω-3 polyunsaturated fatty acids (PUFAs), contributing to the decreases in TGs with high DB#. Thus, an HFD had profound impacts on circulating TG profiles. Some of these changes were at least partly explained by decreased hepatic SCD activity and depleted ω-3 PUFA.

Hepatic stearoyl-CoA desaturase-1 deficiency induces fibrosis and hepatocellular carcinoma-related gene activation under a high carbohydrate low fat diet

Stearoyl-CoA desaturase-1 (SCD1) is a pivotal enzyme in lipogenesis, which catalyzes the synthesis of monounsaturated fatty acids (MUFA) from saturated fatty acids, whose ablation downregulates lipid synthesis, preventing steatosis and obesity. Yet deletion of SCD1 promotes hepatic inflammation and endoplasmic reticulum stress, raising the question of whether hepatic SCD1 deficiency promotes further liver damage, including fibrosis. To delineate whether SCD1 deficiency predisposes the liver to fibrosis, cirrhosis, and hepatocellular carcinoma (HCC), we employed in vivo SCD1 deficient global and liver-specific mouse models fed a high carbohydrate low-fat diet and in vitro established AML12 mouse cells. The absence of liver SCD1 remarkably increased the saturation of liver lipid species, as indicated by lipidomic analysis, and led to hepatic fibrosis. Consistently, SCD1 deficiency promoted hepatic gene expression related to fibrosis, cirrhosis, and HCC. Deletion of SCD1 increased the circulating levels of Osteopontin, known to be increased in fibrosis, and alpha-fetoprotein, often used as an early marker and a prognostic marker for patients with HCC. De novo lipogenesis or dietary supplementation of oleate, an SCD1-generated MUFA, restored the gene expression related to fibrosis, cirrhosis, and HCC. Although SCD1 deficient mice are protected against obesity and fatty liver, our results show that MUFA deprivation results in liver injury, including fibrosis, thus providing novel insights between MUFA insufficiency and pathways leading to fibrosis, cirrhosis, and HCC under lean non-steatotic conditions.

Temporal-Regulation of Serum Lipids and Stearoyl CoA Desaturase and Lipoprotein Lipase mRNA in BALB/cHnn Mice

Databases for genes expressed in humans or cell cultures are being developed as a part of the Human Genome Project. Because genomes respond to nutritional and other environmental variables, quantitative analyses of mRNA abundance under defined nutritional and physiological states are required to understand normal metabolism and to clarify differences between normal and disease phenotypes. Reported here are comparisons of food intake, growth, serum lipids and expression of mRNA for hepatic stearoyl CoA desaturase (Scd1) and heart lipoprotein lipase (Lpl) in female BALB/cHnn mice following food deprivation and refeeding at the end of 2 wk of feeding semipurified diets with 3, 10 or 20% corn oils. Body weights and utilization of dietary energy were similar for mice fed all three diets. There were no differences in serum lipid concentrations associated with the level of dietary fat during subsequent food deprivation and refeeding, but significant differences in serum triglycerides and total serum cholesterol were observed between food-deprived and fed mice. Heart lipoprotein lipase and hepatic Scd1 mRNA expression levels were affected significantly by concentration of corn oil and by time after eating. These and other studies examining gene regulation by dietary variables and nutrient availability are discussed in relation to development of diet-regulated gene databases for laboratory animals fed semipurified diets.

Increased Expression of Hepatic Stearoyl-CoA Desaturase (SCD)-1 and Depletion of Eicosapentaenoic Acid (EPA) Content following Cytotoxic Cancer Therapy Are Reversed by Dietary Fish Oil.

Cancer treatment evokes impediments to liver metabolism that culminate in fatty liver. This study determined hepatic fatty acid composition and expression of genes and mediators involved in lipid metabolism following chemotherapy treatment. Female rats bearing the Ward colon tumor were administered Irinotecan (CPT-11) +5-fluorouracil (5-FU) and maintained on a control diet or a diet containing eicosapentaenoic acid (EPA) + docosahexaenoic acid (DHA) (2.3 g/100 g fish oil). Healthy animals provided with a control diet served as a reference group. Livers were collected one week after chemotherapy. Triacylglycerol (TG), phospholipid (PL), ten lipid metabolism genes, leptin, and IL-4 were measured. Chemotherapy increased TG content and reduced EPA content in the liver. Expression of SCD1 was upregulated by chemotherapy, while dietary fish oil downregulated its expression. Dietary fish oil down-regulated expression of the fatty acid synthesis gene FASN, while restoring the long chain fatty acid converting genes FADS2 and ELOVL2, and genes involved in mitochondrial β-oxidation (CPT1α) and lipid transport (MTTP1), to values similar to reference animals. Neither leptin nor IL-4 were affected by chemotherapy or diet. Depletion of EPA is associated with pathways evoking enhanced TG accumulation in the liver. Restoring EPA through diet may pose a dietary strategy to attenuate chemotherapy-associated impediments in liver fatty acid metabolism.

Hepatic Stearoyl‐CoA desaturase deficiency‐mediated induction of the insulin‐like growth factor‐binding protein 1 requires FGF21

Stearoyl‐CoA desaturase‐1 (SCD1) catalyzes the rate‐limiting step in the biosynthesis of monounsaturated acids and is a key regulator of systemic glucose metabolism. Hepatic deletion of Scd1protects mice from high‐carbohydrate diet (HCD)‐induced hepatic steatosis and adiposity in part by suppressing hepatic lipogenesis, increasing adipose tissue lipogenesis, and increasing systemic glucose uptake. However, the mechanism leading to these phenotypes is unclear. Given that high carbohydrate diets can lead to chronic metabolic diseases such as obesity, diabetes, and hepatic steatosis, it is critical to understand how SCD1 deficiency alters metabolic pathways to produce metabolically beneficial phenotypes. Here we show that hepatic SCD1 deficiency enhances tissue glucose uptake and is correlated with dramatic increases in the expression and plasma levels of the fibroblast growth factor 21 (FGF21), and Insulin growth factor binding protein‐1 (IGFBP1), both liver derived insulin‐sensitizing hormones that are known to regulate whole body lipid and glucose homeostasis. Feeding both male and female LKO mice with triolein, but not tristearin, supplemented HCD reduced Fgf21 and Igfbp1 expression and restored plasma glucose levels. Inhibition of SCD activity in primary hepatocytes induced the expression of Fgf21 and Igfbp1 which was repressed by treatment with oleate but not stearate. Moreover, we show that the hepatic stearoyl‐CoA desaturase deficiency‐mediated induction of the Igfbp1 is through the oleate‐FGF21 axis.

Stearoyl-CoA desaturase 1: A potential target for non-alcoholic fatty liver disease?-perspective on emerging experimental evidence.

Non-alcoholic fatty liver disease (NAFLD) is a progressive disease and one of the leading causes of death. An unnamed disease has become a global epidemic disease of public health concern. This spectrum of diseases manifests itself with initial accumulation of excessive triglycerides (due to de novo lipogenesis) in the hepatocytes, leading to simple steatosis. Although its aetiology is multi-factorial, lifestyle changes (diet and physical activity) are considered to be the key thriving factors. In this context, high fructose consumption is associated with an increased risk for developing NAFLD in humans, while high-fructose feeding to experimental animals results in hepatic steatosis and non-alcoholic steatohepatitis, by increasing hepatic lipogenesis. Among several lipogenic genes, the endoplasmic reticulum-bound stearoyl-CoA desaturase 1 (SCD1) is the key determinant of triglycerides biosynthesis pathway, by providing monounsaturated fatty acids, through the incorporation of a double bond at the delta-9 position of saturated fatty acids, specifically, palmitic (C16:0) and stearic (C18:0) acids, yielding palmitoleic (C16:1) and oleic (C18:1) acids, respectively. Various experimental studies involving SCD1 gene knockout and diet-induced rodent models have demonstrated that SCD1 plays a key role in the development of NAFLD, by modulating hepatic lipogenesis and thus triglyceride accumulation in the liver. Several pharmacological and dietary intervention studies have shown the benefits of inhibiting hepatic SCD1 in the pathogenesis of NAFLD. In this review, we give an overview of SCD1 in NAFLD, based on the current experimental evidence and the translational applicability of SCD1 inhibition in human NAFLD conditions, besides discussing the limitations and way-forward.

Voluntary exercise training improves body weight of leptin-deficient ob/ob mice by altering hepatic stearoyl-CoA desaturase 1 and deleted in breast cancer 1 protein levels.

[Purpose]Deleted in breast cancer 1 (DBC1) ablation causes obesity, and stearoyl-CoA desaturase 1 (SCD1) induces the biosynthesis of monounsaturated fatty acids. This study examined whether voluntary wheel running (VWR) alters SCD-1 and DBC1 protein levels in the liver of leptin-deficient ob/ob mice.[Methods]Twenty-five Ob/Ob mice were divided into two groups (ob/ob-Sed and ob/ob-Ex). The expression of DBC1 and SCD1 in the mouse liver was determined using western blotting.[Results]After 10 weeks, VWR significantly reduced body weight without affecting the fatty acid synthase and CD36 protein levels. The average daily running distance was 4.0±1.0 km/day. This improvement was associated with changes in the hepatic SCD1 and DBC1 levels. Hepatic SCD-1 protein levels increased significantly, and DBC1 protein levels decreased in ob/ob-Sed animals. On the other hand, VWR inhibited the obesity-induced increase in SCD1 expression and impaired the obesity-induced decrease in DBC1 expression in the liver of leptin-deficient ob/ob mice.[Conclusion]This is the first study showing that VWR has strong effects on hepatic SCD1 and DBC1 in ob/ob mice, and provides key insights into the effects of exercise on obesity.

Phytogenic Water Additives Improve Broiler Growth Performance via Modulation of Intermediary Metabolism-Related Signaling Pathways.

Simple SummaryGlobal concern around and heightened sensitivity to emerging drug-resistant superbugs have energized scientists to search for new alternatives to in-feed antibiotics. Powered by consumer demand for natural products and due to their beneficial effects on growth performances, phytogenics have become very popular and favorable alternatives. However, their mode of action has not been fully defined. Here, we showed that supplementation of phytogenics (AVSSL and SG) in water modulates peripheral metabolic pathways (reduction in hepatic fatty acid synthesis, mobilization of fat stores, and enhancement of muscle protein synthesis), which might explain, at least partly, their effect on feed efficiency improvement in broilers. A ban on the use of antibiotic growth promoters (AGPs) has fueled and promoted scientific research towards the identification of reliable and effective alternatives. The supplementation of phytogenics AV/SSL12 (AVSSL) and Superliv Gold (SG) in water has been shown to improve broiler feed efficiency (FE) via modulation of hypothalamic neuropeptides. However, their effects on peripheral metabolic pathways are still unknown. The present study was undertaken to determine the effects of AVSSL and SG on lipid and protein metabolism-associated pathways in various tissues. Day-old male Cobb 500 chicks (n = 288) were randomly assigned to 3 treatment groups, with 8 replicates of 12 birds each. The treatment groups were fed a basal diet and supplemented with AVSSL or SG in the drinking water at a rate of 2, 4, and 7 mL/100 birds/d during the starter, grower, and finisher phases, respectively. The control group were fed a basal diet with no additive supplementation. On d 35, liver, adipose, and muscle tissue were collected from one bird per pen (8 birds/group). Data were analyzed using Student’s T-test to compare one treatment group to the control using Graph Pad Prism version 6.0 for Windows. In the liver, the levels of phosphorylated acetyl-CoA carboxylase alpha (ACCα) were significantly increased in both the AVSSL and SG groups compared to the control. The hepatic expression of sterol regulatory element-binding protein cleavage-activating protein (SCAP) was significantly downregulated in both treated groups compared to the control. AVSSL supplementation downregulated the hepatic expression of SREBP-2 and adiponectin (AdipoQ), while SG administration upregulated hepatic AdipoR1/R2 mRNA abundances compared to the untreated group. Both AVSSL and SG treatments upregulated hepatic stearoyl-CoA desaturase-1 (SCD-1) gene expression compared to their untreated counterparts. In the adipose tissue, the levels of phosphorylated hormone-sensitive lipase (HSL) at Ser855/554 site were increased in both the AVSSL and SG groups compared to the control. However, ATGL protein expression was decreased in SG compared to the untreated group. In the muscle, the levels of phosphorylated mechanistic target of rapamycin (mTOR) were increased in the AVSSL, but decreased in the SG group compared to the control. Collectively, these data indicate that supplementation of the phytogenics AVSSL and SG in water reduced hepatic lipogenesis-related proteins and increased adipose tissue lipolysis- and muscle protein synthesis-associated targets, which might explain, at least partially, the improvement in FE observed in previous research.

Maternal High-Fat Diet Leads to Non-alcoholic Fatty Liver Disease Through Upregulating Hepatic SCD1 Expression in Neonate Rats.

Non-alcoholic fatty liver disease (NAFLD) has become the leading cause of liver disease in children, with evidence that the maternal diet and the early life nutritional environment are potential risk for such disease. This study was aimed to investigate the effects of maternal high-fat diet (HFD) on the occurrence of NAFLD in offspring rats and the underlying mechanisms. In this study, the incidence of NAFLD was compared in F1 offspring rats between the maternal HFD group and standard chow (SC) group. In addition, the expression levels of inflammatory cytokines in the placenta, in the umbilical cord blood, and in the livers of neonate offsprings were compared between two groups. HepG2 cells were treated with recombinant IL6 (rIL6) to assess stearoyl-CoA desaturase 1 (SCD1) expression and lipid synthesis in an inflammatory condition. Lipid accumulation was assayed in both SCD1 overexpression and interference HepG2 cells as well as in neonatal rats. Our results showed that HFD exposure before and throughout the pregnancy induced the elevated hepatic TG content of F1 neonates. The levels of inflammatory cytokines in the placenta, umbilical cord blood, and the livers of HFD F1 neonates were significantly higher than those of the SC group. In addition, rIL6 treatment led to TG accumulation accompanied by the upregulation of SCD1 in HepG2 cell lines. Overexpression of SCD1 led to the accumulation of TG contents in HepG2 cells, whereas Scd1 knockdown attenuated the effects of rIL6 treatment. Overexpression of SCD1 in F1 neonatal rats led to hepatic lipid accumulation. Our study indicated that maternal HFD led to intrauterine inflammation, which subsequently caused transgenerationally abnormal hepatic lipid metabolism of F1 neonates. This modulation might be mediated by upregulating SCD1 expression in hepatic cells.

Arachidyl amido cholanoic acid improves liver glucose and lipid homeostasis in nonalcoholic steatohepatitis via AMPK and mTOR regulation.

BACKGROUNDArachidyl amido cholanoic acid (Aramchol) is a potent downregulator of hepatic stearoyl-CoA desaturase 1 (SCD1) protein expression that reduces liver triglycerides and fibrosis in animal models of steatohepatitis. In a phase IIb clinical trial in patients with nonalcoholic steatohepatitis (NASH), 52 wk of treatment with Aramchol reduced blood levels of glycated hemoglobin A1c, an indicator of glycemic control.AIMTo assess lipid and glucose metabolism in mouse hepatocytes and in a NASH mouse model [induced with a 0.1% methionine and choline deficient diet (0.1MCD)] after treatment with Aramchol.METHODSIsolated primary mouse hepatocytes were incubated with 20 μmol/L Aramchol or vehicle for 48 h. Subsequently, analyses were performed including Western blot, proteomics by mass spectrometry, and fluxomic analysis with 13C-uniformly labeled glucose. For the in vivo part of the study, male C57BL/6J mice were randomly fed a control or 0.1MCD for 4 wk and received 1 or 5 mg/kg/d Aramchol or vehicle by intragastric gavage for the last 2 wk. Liver metabolomics were assessed using ultra-high-performance liquid chromatography-time of flight-MS for the determination of glucose metabolism-related metabolites.RESULTSCombination of proteomics and Western blot analyses showed increased AMPK activity while the activity of nutrient sensor mTORC1 was decreased by Aramchol in hepatocytes. This translated into changes in the content of their downstream targets including proteins involved in fatty acid (FA) synthesis and oxidation [P-ACCα/β(S79), SCD1, CPT1A/B, HADHA, and HADHB], oxidative phosphorylation (NDUFA9, NDUFB11, NDUFS1, NDUFV1, ETFDH, and UQCRC2), tricarboxylic acid (TCA) cycle (MDH2, SUCLA2, and SUCLG2), and ribosome (P-p70S6K[T389] and P-S6[S235/S236]). Flux experiments with 13C-uniformely labeled glucose showed that TCA cycle cataplerosis was reduced by Aramchol in hepatocytes, as indicated by the increase in the number of rounds that malate remained in the TCA cycle. Finally, liver metabolomic analysis showed that glucose homeostasis was improved by Aramchol in 0.1MCD fed mice in a dose-dependent manner, showing normalization of glucose, G6P, F6P, UDP-glucose, and Rbl5P/Xyl5P.CONCLUSIONAramchol exerts its effect on glucose and lipid metabolism in NASH through activation of AMPK and inhibition of mTORC1, which in turn activate FA β-oxidation and oxidative phosphorylation.

Germinated barley downregulates hepatic stearoyl-CoA desaturase-1 enzyme gene expression in a hepatic steatohepatitis rat model.

Steatohepatitis, fibrosis, and cirrhosis are common pathological features in the progression of hepatic steatosis. In the current work, we investigated the effect of germinated barely on the structure and function of the liver and its regulatory mechanism on SDC1 gene expression in a steatohepatitis rat model. Forty-eight adult male white Wistar rats were randomly divided into four groups: Group I, control; Group II, rats fed a germinated barley diet; Group III, rats fed a high-fat diet (HFD); and Group IV, rats fed both germinated barley (GB) and a high-fat diet for 14weeks. Biochemical, histopathological, immunohistochemical, and morphometric studies, as well as qRT-PCR, were used to analyze the effect of germinated barley on steatohepatitis. The rats in Group IV had a lower liver index percentage and improved altered lipid profile and liver function tests compared to those in Group III. Supplementation of GB with a HFD ameliorated the histopathological features in the livers of rats fed a HFD, decreased the percentage of CD68-positive macrophages, and lowered the upregulated expression of SDC1. Supplementation of a HFD with GB prohibited the deterioration of liver function, lipid profile, and alteration of liver structure; it also decreased the associated hepatic inflammation and downregulated SDC1 in liver tissue.

Increased intestinal permeability exacerbates sepsis through reduced hepatic SCD-1 activity and dysregulated iron recycling

Inflammatory bowel disease is associated with changes in the mucosal barrier, increased intestinal permeability, and increased risk of infections and sepsis, but the underlying mechanisms are incompletely understood. Here, we show how continuous translocation of gut microbial components affects iron homeostasis and facilitates susceptibility to inflammation-associated sepsis. A sub-lethal dose of lipopolysaccharide results in higher mortality in Mucin 2 deficient (Muc2−/−) mice, and is associated with elevated circulatory iron load and increased bacterial translocation. Translocation of gut microbial components attenuates hepatic stearoyl CoA desaturase-1 activity, a key enzyme in hepatic de novo lipogenesis. The resulting reduction of hepatic saturated and unsaturated fatty acid levels compromises plasma membrane fluidity of red blood cells, thereby significantly reducing their life span. Inflammation in Muc2−/− mice alters erythrophagocytosis efficiency of splenic macrophages, resulting in an iron-rich milieu that promotes bacterial growth. Our study thus shows that increased intestinal permeability triggers a cascade of events resulting in increased bacterial growth and risk of sepsis.

Hepatic stearoyl CoA desaturase 1 deficiency increases glucose uptake in adipose tissue partially through the PGC-1α–FGF21 axis in mice

Increased carbohydrate consumption increases hepatic de novo lipogenesis, which has been linked to the development of chronic metabolic diseases, including obesity, hepatic steatosis, and insulin resistance. Stearoyl CoA desaturase 1 (SCD1) is a critical lipogenic enzyme that catalyzes the synthesis of two monounsaturated fatty acids, oleate and palmitoleate, from the saturated fatty acids stearate and palmitate, respectively. SCD1-deficient mouse models are protected against diet-induced adiposity, hepatic steatosis, and hyperglycemia. However, the mechanism of this protection by SCD1 deficiency is unclear. Using liver-specific SCD1 knockout (LKO) mice fed a high-carbohydrate, low-fat diet, we show that hepatic SCD1 deficiency increases systemic glucose uptake. Hepatic SCD1 deficiency enhanced glucose transporter type 1 (GLUT1) expression in the liver and also up-regulated GLUT4 and adiponectin expression in adipose tissue. The enhanced glucose uptake correlated with increased liver expression and elevated plasma levels of fibroblast growth factor 21 (FGF21), a hepatokine known to increase systemic insulin sensitivity and regulate whole-body lipid metabolism. Feeding LKO mice a triolein-supplemented but not tristearin-supplemented high-carbohydrate, low-fat diet reduced FGF21 expression and plasma levels. Consistently, SCD1 inhibition in primary hepatocytes induced FGF21 expression, which was repressed by treatment with oleate but not palmitoleate. Moreover, deletion of the transcriptional coactivator PPARγ coactivator 1α (PGC-1α) reduced hepatic and plasma FGF21 and white adipocyte tissue-specific GLUT4 expression and raised plasma glucose levels in LKO mice. These results suggest that hepatic oleate regulates glucose uptake in adipose tissue either directly or partially by modulating the hepatic PGC-1α-FGF21 axis.

Hepatic Stearoyl-CoA desaturase-1 deficiency-mediated activation of mTORC1- PGC-1\u03b1 axis regulates ER stress during high-carbohydrate feeding

Stearoyl CoA desaturase 1 (SCD1) is a key enzyme in lipogenesis as it catalyzes the synthesis of monounsaturated fatty acids (MUFAs), mainly oleate (18:1n9) and palmitoleate (16:1n7) from saturated fatty acids (SFA), stearate (18:0) and palmitate (16:0), respectively. Studies on SCD1 deficiency in mouse models demonstrated beneficial metabolic phenotypes such as reduced adiposity and improved glucose tolerance. Even though, SCD1 represents a potential target to resolve obesity related metabolic diseases; SCD1 deficiency causes endoplasmic reticulum (ER) stress and activates unfolded protein response (UPR). The induction of ER stress in response to SCD1 deficiency is governed by the cofactor, PGC-1α. However, the mechanism by which SCD1 deficiency increases PGC-1α and subsequently induces ER stress still remains elusive. The present study demonstrates that despite reduced lipogenesis, liver specific SCD1 deficiency activates the mechanistic target of rapamycin complex 1 (mTORC1) along with induction of PGC-1α and ER stress. Further, mTORC1 inhibition attenuates SCD1 deficiency-mediated induction of both PGC-1α and ER stress. Similar observations were seen by restoring endogenously synthesized oleate, but not palmitoleate, suggesting a clear mTORC1-mediated regulation of ER stress during SCD1 deficiency. Overall, our results suggest a model whereby maintaining adequate levels of hepatic oleate is required to suppress mTORC1-mediated ER stress. In addition, the activation of mTORC1 by SCD1 deficiency reveals an important function of fatty acids in regulating different cellular processes through mTORC1 signaling.

Effects of overfeeding on the fatty acid profile and stearoyl-CoA desaturase-1 indices in the liver and subcutaneous adipose tissue in cats.

To evaluate the effect of overfeeding on fatty acid distribution and metabolism, especially stearoyl-CoA desaturase-1 (SCD-1) indices, 8 cats in the experimental and control groups (4 per group) were evaluated in this study. The experiments involved feeding the experimental group cats twice their daily energy requirement with a commercial diet for 4 weeks. The control group was fed the estimated daily energy requirement with the same diet. Body weight, feline body mass index, body condition score, several zoometry measurements, and plasma metabolites/hepatic injury markers were measured in all the cats before and after the experiment. In addition, the fatty acid profiles in the liver and subcutaneous adipose tissue were measured after the experiment. After 4 weeks of overfeeding, the experimental group demonstrated significant increases in hepatic C18:1, plasma triglyceride, and nonesterified fatty acid (NEFA) concentrations and in alanine aminotransferase activity. Furthermore, hepatic SCD-1 indices were positively correlated with body weight, feline body mass index, body condition score, and plasma NEFA concentration, although subcutaneous adipose tissue did not demonstrate any increase in SCD-1 indices in this study. The increase in hepatic SCD-1 indices might be enhanced by the inflow of plasma NEFA into the liver, and NEFA toxicity might stimulate C18:1 synthesis by SCD-1.

Long-term administration of olanzapine induces adiposity and increases hepatic fatty acid desaturation protein in female C57BL/6J mice.

Objective(s):Weight gain and metabolic disturbances such as dyslipidemia, are frequent side effects of second-generation antipsychotics, including olanzapine. This study examined the metabolic effects of chronic olanzapine exposure. In addition, we investigated the hepatic fatty acid effects of olanzapine in female C57BL/6J mice fed a normal diet.Materials and Methods:Female C57BL/6J mice orally received olanzapine or normal saline for 7 weeks. The effects of long-term olanzapine exposure on body weight changes, food efficiency, blood glucose, triglyceride (TG), insulin, and leptin levels were observed. Hepatic TG and abdominal fat mass were investigated, and fat cell morphology was analyzed through histopathological methods. The levels of protein markers of fatty acid regulation in the liver, namely fatty acid synthase (FAS) and stearoyl-CoA desaturase-1 (SCD-1), were measured.Results:Olanzapine treatment increased the food intake of the mice as well as their body weight. Biochemical analyses showed that olanzapine increased blood TG, insulin, leptin, and hepatic TG. The olanzapine group exhibited increased abdominal fat mass and fat cell enlargement in abdominal fat tissue. Western blotting of the mouse liver revealed significantly higher (1.6-fold) levels of SCD-1 in the olanzapine group relative to the control group; by contrast, FAS levels in the two groups did not differ significantly.Conclusion:Enhanced lipogenesis triggered by increased hepatic SCD-1 activity might be a probable peripheral mechanism of olanzapine-induced dyslipidemia. Some adverse metabolic effects of olanzapine may be related to the disturbance of lipid homeostasis in the liver.

Vitamin A Improves Hyperglycemia and Glucose-Intolerance through Regulation of Intracellular Signaling Pathways and Glycogen Synthesis in WNIN/GR-Ob Obese Rat Model.

Vitamin A and its metabolites modulate insulin resistance and regulate stearoyl-CoA desaturase 1 (SCD1), which are also known to affect insulin resistance. Here, we tested, whether vitamin A-mediated changes in insulin resistance markers are associated with SCD1 regulation or not. For this purpose, 30-week old male lean and glucose-intolerant obese rats of WNIN/GR-Ob strain were given either a stock or vitamin A-enriched diet, i.e. 2.6 mg or 129 mg vitamin A/kg diet, for 14 weeks. Compared to the stock diet, vitamin A-enriched diet feeding improved hyperglycemia and glucose-clearance rate in obese rats and no such changes were seen in lean rats receiving identical diets. These changes were corroborated with concomitant increase in circulatory insulin and glycogen levels of liver and muscle (whose insulin signaling pathway genes were up-regulated) in obese rats. Further, the observed increase in muscle glycogen content in these obese rats could be explained by increased levels of the active form of glycogen synthase, the key regulator of glycogen synthesis pathway, possibly inactivated through increased phosphorylation of its upstream inhibitor, glycogen synthase kinase. However, the unaltered hepatic SCD1 protein expression (despite decreased mRNA level) and increased muscle-SCD1 expression (both at gene and protein levels) suggest that vitamin A-mediated changes on glucose metabolism are not associated with SCD1 regulation. Chronic consumption of vitamin A-enriched diet improved hyperglycemia and glucose-intolerance, possibly, through the regulation of intracellular signaling and glycogen synthesis pathways of muscle and liver, but not associated with SCD1.

Lipidomic and metabolic changes in the P4-type ATPase ATP10D deficient C57BL/6J wild type mice upon rescue of ATP10D function.

BackgroundSequence variants near the human gene for P4-type ATPase, class V, type 10D (ATP10D) were shown to significantly associate with circulating hexosylceramide d18:1/16:0 and d18:1/24:1 levels, obesity, insulin resistance, plasma high density lipoprotein (HDL), coronary stenotic index and intracranial atherosclerotic index. In mice Atp10d is associated with HDL modulation and C57BL/6 mice expressing a truncated, non-functional form of ATP10D easily develop obesity and insulin resistance on high-fat diet.ResultsWe analyzed metabolic differences of ATP10D deficient C57BL/6J wild type and ATP10D transgenic C57BL/6J BAC129 mice. ATP10D transgenic mice gain 25% less weight on high-fat diet concomitant with a reduced increase in fat cell mass but independent of adipocyte size change. ATP10D transgenic mice also had 26% lower triacylglycerol levels with approximately 76% bound to very low density lipoprotein while in ATP10D deficient wild type mice 57% are bound to low density lipoprotein. Furthermore increased oxygen consumption and CO2 production, 38% lower glucose and 69% lower insulin levels and better insulin sensitivity were observed in ATP10D transgenic mice. Besides decreased hexosylceramide species levels were detected. Part of these effects may be due to reduced hepatic stearoyl-CoA desaturase 1 (SCD1) expression in ATP10D transgenic mice, which was reflected by altered fatty acid and lipid species patterns. There was a significant decrease in the hepatic 18:1 to 18:0 free fatty acid ratio in transgenic mice. The ratio of 16:1 to 16:0 was not significantly different. Interestingly both ratios were significantly reduced in plasma total fatty acids.SummaryIn summary we found that ATP10D reduces high-fat diet induced obesity and improves insulin sensitivity. ATP10D transgenic mice showed altered hepatic expression of lipid-metabolism associated genes, including Scd1, along with changes in hepatic and plasma lipid species and plasma lipoprotein pattern.

Carrot Juice Administration Decreases Liver Stearoyl-CoA Desaturase 1 and Improves Docosahexaenoic Acid Levels, but Not Steatosis in High Fructose Diet-Fed Weanling Wistar Rats

Non-alcoholic fatty liver disease (NAFLD) is one of the most prevalent liver diseases associated with an altered lifestyle, besides genetic factors. The control and management of NAFLD mostly depend on lifestyle modifications, due to the lack of a specific therapeutic approach. In this context, we assessed the effect of carrot juice on the development of high fructose-induced hepatic steatosis. For this purpose, male weanling Wistar rats were divided into 4 groups, fed either a control (Con) or high fructose (HFr) diet of AIN93G composition, with or without carrot juice (CJ) for 8 weeks. At the end of the experimental period, plasma biochemical markers, such as triglycerides, alanine aminotransferase, and β-hydroxy butyrate levels were comparable among the 4 groups. Although, the liver injury marker, aspartate aminotransferase, levels in plasma showed a reduction, hepatic triglycerides levels were not significantly reduced by carrot juice ingestion in the HFr diet-fed rats (HFr-CJ). On the other hand, the key triglyceride synthesis pathway enzyme, hepatic stearoyl-CoA desaturase 1 (SCD1), expression at mRNA level was augmented by carrot juice ingestion, while their protein levels showed a significant reduction, which corroborated with decreased monounsaturated fatty acids (MUFA), particularly palmitoleic (C16:1) and oleic (C18:1) acids. Notably, it also improved the long chain n-3 polyunsaturated fatty acid, docosahexaenoic acid (DHA; C22:6) content of the liver in HFr-CJ. In conclusion, carrot juice ingestion decreased the SCD1-mediated production of MUFA and improved DHA levels in liver, under high fructose diet-fed conditions. However, these changes did not significantly lower the hepatic triglyceride levels.

Long-term fructose consumption prolongs hepatic stearoyl-CoA desaturase 1 activity independent of upstream regulation in rats

Dietary fructose is considered a risk factor for metabolic disorders, such as fatty liver disease. However, the mechanism underlying the effects of fructose is not well characterized. We investigated the hepatic expression of key regulatory genes related to lipid metabolism following fructose feeding under well-defined conditions. Rats were fed standard chow supplemented with 10% w/v fructose solution for 5 weeks, and killed after chow-fasting and fructose withdrawal (fasting) or chow-fasting and continued fructose (fructose alone) for 14 h. Hepatic deposition of triglycerides was found in rats from both groups. As expected, fructose alone increased mRNA levels of lipogenesis-related genes and correspondingly decreased mRNA levels of lipid oxidative genes in the liver. Interesting, hepatic levels of stearoyl-CoA desaturase (SCD)1 mRNA remained elevated under fructose withdrawn conditions, although expression levels of other genes, including two key transcription factors (carbohydrate response element binding protein (ChREBP) and sterol regulatory element-binding protein (SREBP)-1c) fell to normal levels, indicating that long-term fructose intake increased SCD1 activity, independent of upstream regulatory genes, such as ChREBP and SREBP-1c. In conclusion, SCD1 overexpression in fatty liver disease is not affected by fasting after long-term fructose consumption in rats. Regulation of SCD1 plays an important role in fructose-induced hepatic steatosis.