Dysregulation of the biological clock disrupts the homeostasis of physiological functions, which may lead to the development of various disorders. To investigate the relationship between biological rhythms and disorders, an efficient monitoring method of the biological clock is necessary. In this study, we analyzed the circadian rhythmicity profile of bile acids in urine and investigated whether urinary bile acid (UBA) could reflect the circadian rhythm in liver physiology. Male Wistar-Hannover rats were maintained in metabolic cages under ad lib feeding and later subjected to restricted feeding (in which rats were fed only during light periods). Excreted urine was collected in each session, and bile acid contents were analyzed via an enzyme-based total bile acid assay. UBA content showed diurnal fluctuations under both ad lib and restricted feeding conditions and reached a peak during the dark period of ad lib feeding. In contrast, with restricted feeding, the peak was observed during light periods. Restricted feeding induced an 8-12 h phase shift. Diurnal fluctuation and phase shift by restricted feeding are distinctive features controlled by biological clocks in peripheral tissues. Since bile acids are synthesized in the liver, we propose that UBA might reflect the circadian fluctuation in liver physiology.

The present study investigated whether a single pretreatment with clofibric acid suppresses liver injury in rats after CCl4 intoxication. Rats received a single pretreatment with clofibric acid (100 mg/kg, i.p.) 1 h prior to a CCl4 (1 mL/kg, p.o.) challenge, and were euthanized 24 h after the CCl4 administration. A single pretreatment with clofibric acid effectively suppressed increases in the serum aminotransferase activities and the severity of necrosis following the CCl4 challenge, whereas the pretreatment did not protect against CCl4-induced fatty liver. The clofibric acid pretreatment did not affect blood concentrations of CCl4 in the early stage after CCl4 dosing, or the level of the CCl4 reaching the liver 1 h after the CCl4 challenge. Moreover, the clofibric acid pretreatment did not affect the intensity of the covalent binding of the [14C]CCl4 metabolite to microsomal proteins and lipids. The clofibric acid pretreatment did not alter microsomal cytochrome P450 2E1 activity. Based on these results, we conclude that protection against CCl4-induced hepatocellular necrosis by a clofibric acid pretreatment does not require its repeated administration, and that a single and brief pre-exposure to clofibric acid prior to CCl4 dosing markedly suppresses necrosis without affecting the development and progression of steatosis.

The circadian system regulates sleep/wake cycles, metabolism, mood, and other functions. It also influences medication efficacy. In this study, we studied the chronopharmacological profiles of antidepressants with various modes of action. We also investigated the effects of dosing time on the pharmacological activity of several antidepressants acting on serotonergic, noradrenergic, and/or dopaminergic neurons. C57BL/6 mice were intraperitoneally administered fluoxetine, imipramine, venlafaxine, or bupropion at 08:00 h (morning), 14:00 h (mid-day), 20:00 h (evening), or 02:00 h (mid-night). Antidepressant activity was evaluated by the tail suspension test. All antidepressants reduced immobility, and their activities varied according to the dosing time. Fluoxetine and imipramine induced relatively strong rhythms with high amplitudes. Their maximal effects were observed in the morning and evening, respectively. Venlafaxine and bupropion induced weak rhythms with maximal effects in the evening and dawn, respectively. These results suggest that the antidepressant activity is associated with circadian fluctuation, and antidepressants with different modes of action have different chronopharmacological profiles. They affect locomotor activity in animals placed in novel (unfamiliar) environments. Fluoxetine, imipramine, and venlafaxine reduced locomotor activity, whereas bupropion increased it. The effects on locomotor activity also vary with circadian rhythm, and the tested drugs showed a maximal effect during the light phase. The peak time was different from that in TST. Plasma and brain levels of all drugs were slightly higher in the morning than in the evening. The dosing time dependency of the antidepressant activity did not correlate with the sedative/stimulatory activity or tissue drug level. Therefore, these latter two factors may have only a small impact on circadian antidepressant activity fluctuations. The relative activity of the serotonergic, noradrenergic, and dopaminergic systems may determine the chronopharmacological profiles of each drug. These results suggest the possibility that drug therapy be optimized by considering the dosing time when the antidepressant activity is high and other pharmacological activities leading to adverse effects are low. Further studies using animal models of depression and in clinical settings are necessary to confirm the effects of dosing time on depressed subjects.

Biological rhythms are thought to be related to the pathogenesis and therapy of various diseases including depression. Here we investigated the influence of circadian rhythms on the antidepressant activity of the dual-action serotonin-noradrenaline reuptake inhibitor (SNRI) milnacipran. Rats administered milnacipran in the morning (8:00 a.m.; zeitgeber time [ZT]1) or in the evening (8:00 p.m.; ZT13) were analyzed in a forced swim test (FST). At ZT1, the rats' immobility was reduced and the swimming was increased, whereas at ZT13, their climbing was increased. These results suggest that the serotonergic and noradrenergic systems are preferentially affected at ZT1 and ZT13, respectively by milnacipran. We analyzed the plasma and brain levels of milnacipran after administration, and there were no differences between ZT1 and ZT13. The circadian rhythm of monoamine neurotransmitters was analyzed in several brain regions. The serotonin turnover showed rhythms with a peak during ZT18-ZT22 in hippocampus. The noradrenaline turnover showed rhythms with a peak during ZT22-ZT2. There was a difference of approx. 4 h between the serotonergic and noradrenergic systems. This time difference might be one of the factors that affect the action of milnacipran and contribute to the dosing time-dependent behavioral pattern in the FST.

Circadian disruption affects the pathogenesis and development of various diseases. Depression is one of the most common diseases that relate to circadian rhythm. In this study, we analyzed the effects of daily light/dark (LD) conditions on depression and other symptoms, and also analyzed the mixed effects of LD conditions and corticosterone treatment. Male adult C57BL/6 mice were treated with corticosterone in a normal LD cycle of 12 hours light and 12 hours dark (LD12 : 12), short day conditions of 6 hours light and 18 hours dark (LD6 : 18), or long day conditions of 21 hours light and 3 hours dark (LD21 : 3). The activity rhythms of mice in aberrant LD conditions were entrained within 2 weeks. After 6 weeks of exposure, several behavioral tests were conducted. Corticosterone induced body weight gain and depression-like symptoms. The short or long LD conditions had little effect on vehicle-treated mice behavior. However, the aberrant LD conditions exacerbated the corticosterone-induced symptoms. Mice treated with corticosterone in LD6 : 18 showed exacerbated depression-like symptoms in a novelty suppressed feeding test. On the other hand, LD21 : 3 did not show any effects on mood, but enhanced corticosterone-induced body weight gain. These results indicated that aberrant LD conditions could act as an exacerbating factor for corticosterone-induced symptoms, and that short and long photoperiods induce different psychological and physiological changes. This corticosterone + aberrant LD model could be a useful animal model for investigating the effect of LD conditions on depression, obesity, and other symptoms in stressful circumstances.

The pathogenesis and therapeutics of depression are linked to the operation of the circadian system. Here, we studied the chronopharmacological action of a tricyclic antidepressant, imipramine. Male adult Wistar-Hannover rats were administered imipramine acutely or chronically in the morning or in the evening. The antidepressant action of imipramine was analyzed using the forced swim test (FST). A single dose of imipramine (30 mg/kg) in the morning, but not in the evening, reduced immobility and increased climbing in the FST. The plasma concentrations of imipramine and its metabolite, desipramine, were slightly higher in the morning than in the evening, which might explain the dosing time-dependent action of imipramine. Next, we analyzed the effect of chronic imipramine treatment. Rats received imipramine in the morning or in the evening for 2 weeks. The morning treatment resulted in larger effects in the FST than the evening treatment, and was effective at a dose that was ineffective when administered acutely. The levels of brain α-adrenergic receptors tended to decrease after chronic imipramine treatment. Imipramine might interact with noradrenergic neurons, and this interaction might chronically alter receptor expression. This alteration seemed greater in the morning than in the evening, which might explain the dosing time-dependent action of imipramine.

Matrix metalloproteinase inhibitors (MMPIs) reduced serum triacylglycerol (TAG) levels in streptozotocin-induced diabetic rats and Zucker fa/fa rats in our previous study. However, the mechanisms underlying TAG reduction by MMPIs remain unclear. The present study aimed to elucidate the mechanism by which F81-1144b, an MMPI, lowers serum TAG levels in an animal model of high-sucrose diet (HSD)-induced hypertriglyceridemia. F81-1144b was repeatedly administered to rats fed HSD, and its effects were evaluated on TAG levels in serum and the liver, very low density lipoprotein (VLDL) secretion, de novo fatty acid (FA) synthesis in the liver, and the expression of genes regulating the metabolism of FA, TAG, and VLDL in the liver and serum. F81-1144b lowered TAG levels in serum and the liver, VLDL-TAG secretion, de novo FA synthesis in the liver, and serum levels of insulin and glucose. F81-1144b suppressed the expression of genes related to the de novo synthesis of FA and TAG, key proteins (lipin 1 and apolipoprotein CIII) responsible for VLDL metabolism, and sterol regulatory element-binding protein-1c and carbohydrate response element-binding protein. F81-1144b little affected the expression of genes related directly to the degradation of TAG or FA, but it upregulated that of gene for uncoupling protein 2 in the liver. These results suggest that MMPIs are a novel type of therapeutic agent for the treatment of hypertriglyceridemia, because the metabolic effects of F81-1144b expected from changes in the expression of genes regulating lipid metabolism would alter metabolism differently from those induced by fibrates, niacin, or n-3 FAs.

The disposition of perfluorododecanoic acid (PFDoA), a perfluorocarboxylic acid with 12 carbon atoms, was studied in male rats. Rats received an oral administration of PFDoA at a dose of 50 mg/kg. The body weights of PFDoA-treated rats were slightly less than those of vehicle-treated control rats. PFDoA administration resulted in an increase in liver weight; it was highest at 5 days after the treatment and gradually decreased thereafter. Higher liver weight was observed until 70 days after the treatment. Concentrations of PFDoA in plasma and various tissues were estimated up to 70 days after dosing. A large amount of PFDoA was found in the liver. The PFDoA concentration was 263.94 ± 32.94 μg/g in the liver; the value was 7.93 times higher than that of serum 5 days after treatment. The hepatic PFDoA amount was found to be 29.63% of the dose. A certain amount of PFDoA was found in the brain and adipose tissues where perfluorocarboxylic acids with less than 11 carbon atoms were sparsely distributed. The half-life of PFDoA was 55.3, 49.3, 52.4, 57.1, and 49.8 days for serum, liver, kidneys, brain, and adipose tissue, respectively. PFDoA increased hepatic levels of mRNA for Cyp4A10, Acot1, and Acox1, target genes of PPARα, suggesting that PFDoA can activate PPARα, as was observed with other PFCAs. Elevated levels of these 3 genes were observed 70 days after treatment, and the levels were less than those at 7 days. The differences between PFDoA and PFCAs with less than 11 carbon atoms were discussed.

Estimation of liver damage is important in the pathophysiologica] and toxicological study of liver disease. As a novel, non-invasive markcr of liver darnage, we studicd the effcacy ofurine bile acids (UBA) in a rat model ofliver disease. Thioaeetamide (TAA)-treated rats were used in this study. Single intraperitoneal administration ofhigh-dose TAA induees severe damage to the liver, and thus is used as a model of acute hepatitis. Continuous administration oflow-dose TAA yields mild damage to the liver, and induces cirrhosis and hepatic tumors. In this study, it was found that both acute and chronic administration of TAA was associated with a dose-dependent elevation ofUBA, The elevation of UBA content correlated with the alteration of blood biochemical indicators, and UBA screening showed a remarkable ability to distinguish liver-dainaged rats fi'om healthy rats. In particular, UBA analysis was found to have high sensitivity, spccificity, and positive predictive value for the scrcening ofrats with abnormal serum alkaline phosphatase (ALP) activity due to chronic liver damage, which was confirmcd to include cholestasis and subsequent cirrhosis by liver histological nalysis. In conclusion, we demonstrated that measurement QfUBA is a simple, non-invasive and e('Tective method fbr the screening of cholestasis in TAA-treated rats. We suggest that UBA analysis may have potent applicability fbr monitoring the progress of liver damage in animal models of chronic liver disease, such as cirrhosis and hepatic encephalopathy.

The brain level of perfluorododecanoic acid (PFDoA) was compared with those of perfluorooctanoic acid (PFOA) and perfluorodecanoic acid (PFDA) in rats 9 days after a single oral dose (50 mg/kg). The PFDoA level in the brain was 44.0 ± 2.0 µg/g, which was higher than that in the serum (24.4 ± 1.0 µg/ml). In contrast, the concentrations of PFOA and PFDA in the brain were low (<0.8 and 4.7 ± 0.4 µg/g, respectively), and less than one-tenth of those in the serum. Next, to investigate the effects on brain function, the cognitive function alterations of PFOA, PFDA, and PFDoA were estimated by the novel object recognition test 5-6 days after dosing. A significant decrease in the discrimination index was observed in PFDoA-treated rats while no significant alteration was observed in PFDA- and PFOA-treated rats. The effects of PFDoA were further assessed by other behavioral tests. PFDoA-associated alteration was observed in the elevated-plus maze test, but not in the Y-maze test, open-field test, and forced swim test. A decrease in the discrimination index of the novel object recognition test was dependent on the PFDoA dose and the PFDoA concentration in the brain. PFDoA concentration in the brain was 28.6 ± 2.6 µg/g 30 days after dosing, and a decrease in discrimination index was observed. Taken together, these results suggest that PFDoA distributes in the brain easier than PFOA and PFDA and causes cognitive deficit.

Different monounsaturated fatty acid (MUFA) species have distinct pathophysiological activities. cis-Palmitoleic acid (16:1n-7) was previously reported to improve insulin sensitivity in animal studies. The proportions of hepatic MUFAs are generally considered to reflect changes in the activities of fatty acid modifications (∆9 desaturation and fatty acid elongation). However, hepatic levels of 16:1n-7 are markedly lower than those of oleic acid (18:1n-9). Nevertheless, no convincing explanation has yet been provided for the low level of 16:1n-7. We hypothesized that fatty acid degradation plays a key role in maintaining a low 16:1n-7 proportion in the liver. In order to corroborate the link between β-oxidation and the proportion of 16:1n-7, rats were fed a control diet, fed a fat-free diet to up-regulate fatty acid modifications, but not β-oxidation, or treated with clofibric acid to up-regulate fatty acid modifications and β-oxidation. The nutritional manipulation markedly increased the proportions of 16:1n-7, 18:1n-9, and cis-vaccenic acid (18:1n-7). Although the pharmacological manipulation enhanced fatty acid modifications to largely the same extent as the nutritional manipulation and markedly elevated the proportion of 18:1n-9, those of 16:1n-7 and 18:1n-7 remained largely unchanged. The oxidation rates of 16:1n-7, 18:1n-9, and 18:1n-7 in liver slices were in the following order: 16:1n-7>18:1n-7≑18:1n-9 in control livers, and were increased by the pharmacological manipulation and decreased by the nutritional manipulation. These results strongly suggest that β-oxidation, in concert with fatty acid modifications, plays a key role in regulating the MUFA profile and is crucially involved in maintaining low 16:1n-7 levels in the liver.

The Goto-Kakizaki (GK) rat is widely used as an animal model for spontaneous-onset type 2 diabetes without obesity; nevertheless, little information is available on the metabolism of fatty acids and triacylglycerols (TAG) in their livers. We investigated the mechanisms underlying the alterations in the metabolism of fatty acids and TAG in their livers, in comparison with Zucker (fa/fa) rats, which are obese and insulin resistant. Lipid profiles, the expression of genes for enzymes and proteins related to the metabolism of fatty acid and TAG, de novo synthesis of fatty acids and TAG in vivo, fatty acid synthase activity in vitro, fatty acid oxidation in liver slices, and very-low-density-lipoprotein (VLDL)-TAG secretion in vivo were estimated. Our results revealed that (1) the TAG accumulation was moderate, (2) the de novo fatty acid synthesis was increased by upregulation of fatty acid synthase in a post-transcriptional manner, (3) fatty acid oxidation was also augmented through the induction of carnitine palmitoyltransferase 1a, and (4) the secretion rate of VLDL-TAG remained unchanged in the livers of GK rats. These results suggest that, despite the fact that GK rats exhibit non-obese type 2 diabetes, the upregulation of de novo lipogenesis is largely compensated by the upregulation of fatty acid oxidation, resulting in only moderate increase in TAG accumulation in the liver.

Pathophysiological and nutritional conditions often affect the expression of drug-metabolizing enzymes. SHR/NDmcr-cp (cp/cp) rats (SHR/NDcp) are highly suitable as a metabolic syndrome (MS) model. Nevertheless, little is known about the expression profile of cytochrome P450 (CYP) in the liver of SHR/NDcp. We thus attempted to clarify the expression profile of CYP genes and the effect of fish oil (FO) on this profile in the liver of SHR/NDcp. Lower levels of CYP3A2 mRNA and CYP3A activity (testosterone 6β-hydroxylation) were distinctive features in SHR/NDcp compared with their controls (Wistar Kyoto rats (WKY), spontaneously hypertensive rats (SHR), stroke-prone SHR and lean littermates of SHR/NDcp). Differently from CYP3A2, the expression of other CYP isoforms was largely unchanged in SHR/NDcp. The changes in CYP profile observed in SHR/NDcp are similar to those of patients with diabetes and simple hepatic steatosis. Feeding on FO at a high dose (18.8% in the diet) up-regulated CYP3A2 gene expression and CYP3A activity in the liver; the extent of these increases was greater in SHR/NDcp than in WKY and lean littermates of SHR/NDcp. This effect was not observed with FO at a normal dose (5% in the diet). These results indicate that, in the context of the CYP profile, SHR/NDcp is an animal model that is suitable for studying MS and imply that FO intake is critical in determining the efficacy or adverse effects of drugs in patients with MS.

Fibrates are used in biochemical and pharmacological studies as bioactive tools. Nevertheless, most studies have lacked information concerning the concentrations of fibric acids working inside tissues because a simple and sensitive method is not available for their quantitation. This study aimed to develop a simple and sensitive bioanalytical method for the quantitation of clofibric, bezafibric and fenofibric acids in samples of very small portions of tissues. Fibric acids were extracted into n-hexane-ethyl acetate from tissue homogenates (10 mg of liver, kidney or muscle) or serum (100 µL) and were derivatized with 4-bromomethyl-6,7-dimethoxycoumarin, followed by HPLC with fluorescence detection. These compounds were separated isocratically on a reversed phase with acetonitrile-water. Standard analytical curves were linear over the concentration range of 0.2-20 nmol/10 mg of liver. Precision and accuracy were within acceptable limits. Recovery from liver homogenates ranged from 93.03 to 112.29%. This method enabled the quantitation of fibric acids in 10 mg of liver from rats treated with clofibric acid, bezafibric acid or fenofibrate. From these analytical data, it became clear that there was no large difference in ratio of acyl-CoA oxidase 1 (Acox1) mRNA level to fibric acid content in the liver among the three fibric acids, suggesting that these three fibric acids have similar potency to increase expression of the Acox1 gene, which is a target of peroxisome proliferator-activated receptor α. Thus, the proposed method is a simple, sensitive and reliable tool for the quantitation of fibric acids working in vivo inside livers.

Fibrates have been reported to elevate the hepatic proportion of oleic acid (18:1n-9) through inducing stearoyl-CoA desaturase (SCD). Despite abundant studies on the regulation of SCD in the liver, little is known about this issue in the small intestine. The present study aimed to investigate the effect of clofibric acid on the fatty acid profile, particularly monounsaturated fatty acids (MUFA), and the SCD expression in intestinal mucosa. Treatment of rats with a diet containing 0.5% (w/w) clofibric acid for 7 days changed the MUFA profile of total lipids in intestinal mucosa; the proportion of 18:1n-9 was significantly increased, whereas those of palmitoleic (16:1n-7) and cis-vaccenic (18:1n-7) acids were not changed. Upon the treatment with clofibric acid, SCD was induced and the gene expression of SCD1, SCD2, and fatty acid elongase (Elovl) 6 was up-regulated, but that of Elovl5 was unaffected. Fat-free diet feeding for 28 days increased the proportions of 16:1n-7 and 18:1n-7, but did not effectively change that of 18:1n-9, in intestinal mucosa. Fat-free diet feeding up-regulated the gene expression of SCD1, but not that of SCD2, Elovl6, or Elovl5. These results indicate that intestinal mucosa significantly changes its MUFA profile in response to challenges by clofibric acid and a fat-free diet and suggest that up-regulation of the gene expression of SCD along with Elovl6 is indispensable to elevate the proportion of 18:1n-9 in intestinal mucosa.

Stroke-prone spontaneously hypertensive rats (SHRSP) are utilized as models for study of the pathogenesis of not only stroke and cardiovascular disorders but also atherosclerosis and metabolic syndrome. Basic information on the profiles of fatty acids and lipid classes in the liver is indispensable to use SHRSP as a model of disorder of lipid metabolism; nevertheless, detailed information on the metabolism of triacylglycerols (TAGs) and fatty acids in the liver of SHRSP is lacking. This study aimed to characterize profiles of lipid classes and fatty acids and to explore the mechanism underlying the characteristic alterations in metabolism of TAGs and fatty acids in the liver of SHRSP, in comparison with spontaneously hypertensive rats (SHR). The characteristic changes observed in SHRSP were (1) markedly lower hepatic TAG contents; (2) altered expressions of genes encoding three enzymes responsible for the control of TAG level, namely, adipose triglyceride lipase (for TAG degradation; up-regulated), carnitine palmitoyltransferase 1a (for fatty acid β-oxidation; up-regulated) and long-chain acyl-CoA synthetase 3 (for glycerolipid synthesis; down-regulated); (3) evidently lower contents and proportions of monounsaturated fatty acids, in particular cis-vaccenic acid (18:1n-7), in the liver and serum; and (4) down-regulation of palmitoleoyl-CoA chain elongase, which is necessary for the biosynthesis of 18:1n-7, in the liver. From the above observations, we concluded that there are significant differences in profiles of lipid classes and fatty acids between SHRSP and SHR, and that altered characteristics in SHRSP are likely responsible for increases in TAG hydrolysis and β-oxidation, and decreases in TAG synthesis and 18:1n-7 synthesis.

Hepatic triacylglycerol (TAG) homeostasis is maintained by carefully regulated balance between its synthesis and disposal. Impairment in this balance causes steatosis. The aims of this study were i) to uncover whether fibrates control TAG concentration through the action of adipose triglyceride lipase (ATGL) and ii) to compare the potency of the effects on ATGL expression and TAG concentration among fenofibrate, bezafibrate, and clofibric acid in the liver of rats. Treatments of rats with the three fibrates induced ATGL and concomitantly decreased hepatic TAG concentration. The upregulation of ATGL was likely mediated through the activation of peroxisome proliferator-activated receptor α. Fibrates also expanded capacity of fatty acid β-oxidation. Importantly, three fibric acids (fenofibric, bezafibric, and clofibric acids) that are active metabolites formed in the liver exhibited almost the same potency to elevate ATGL expression in vivo, despite the fact that there were considerable differences in this regard among fenofibrate, bezafibrate, and clofibric acid when compared on the basis of their dosage. These results suggest that ATGL represents a potential therapeutic target for ameliorating hepatic steatosis and that fibric acids are promising agents to ameliorate and/or protect against hepatic steatosis.

SHR/NDmcr-cp ( cp / cp ) rats (SHR/NDcp) are an animal model of metabolic syndrome. A previous study of ours revealed drastic increases in the mass of palmitic (16:0), oleic (18:1n-9), palmitoleic (16:1n-7), cis -vaccenic (18:1n-7) and 5,8,11-eicosatrienoic acids in the liver of SHR/NDcp. However, detailed information on the class of lipid accumulated and the mechanism responsible for the overproduction of the accumulated lipid in the liver was not obtained. This study aimed to characterize the class of lipid accumulated and to explore the mechanism underlying the lipid accumulation in the liver of SHR/NDcp, in comparison with SHR/NDmcr-cp (+/+) (lean hypertensive littermates of SHR/NDcp) and Wistar Kyoto rats. In the liver of SHR/NDcp, de novo synthesis of fatty acids (16:0, 18:1n-9 and 16:1n-7) and triacylglycerol (TAG) synthesis were up-regulated and fatty acid β-oxidation was down-regulated. These perturbations of lipid metabolism caused fat accumulation in hepatocytes and accumulation of TAG, which were enriched with 16:0, 18:1n-9 and 16:1n-7, in the liver of SHR/NDcp. On the other hand, no changes were found in hepatic contents of diacylglycerol and unesterified fatty acid (FFA); among FFA, there were no differences in the hepatic concentrations of unesterified 16:0 and stearic acid between SHR/NDcp and two other groups of rats. Moreover, little change was brought about in the expression of genes responsive to endoplasmic reticulum stress in the liver of SHR/NDcp. These results may reinforce the pathophysiological role of stearoyl-CoA desaturase 1 and fatty acid elongase 6 in the liver of SHR/NDcp.