Heterozygosity for leptin receptor (fa) accelerates hepatic triglyceride accumulation without hyperphagia in Zucker rats

Himeno, Katsuro; Seike, Masataka; Fukuchi, Satoshi; Masaki, Takayuki; Kakuma, Tatsuyuki; Sakata, Toshiie; Yoshimatsu, Hironobu

doi:10.1016/j.orcp.2008.10.003

Cited by 6 publications

(12 citation statements)

References 20 publications

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“…Serum differences were found for total and direct bilirubin and p-Cholinesterase; an approximately ten-fold increase in cholesterol and triglycerides was found in Obese Zucker versus MCD rats. The serum levels of cholesterol and triglyceride were comparable with those reported previously [21,22]. A marked higher levels of TNF-alpha were detectable in MCD when compared with Obese Zucker rats.…”

Section: Resultssupporting

confidence: 88%

Fatty Acid Desaturase Involvement in Non-Alcoholic Fatty Liver Disease Rat Models: Oxidative Stress Versus Metalloproteinases

Palladini

Pasqua²,

Berardo³

et al. 2019

Nutrients

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We investigated changes in fatty acid desaturases, D5D, D6D, D9-16D and D9-18D, and their relationship with oxidative stress, matrix metalloproteinases (MMPs) and serum TNF-alpha in two rat models of non-alcoholic fatty liver disease NAFLD. Eight-week-old male Wistar rats fed for 3 weeks with methionine-choline–deficient (MCD) diet and eleven-week-old Obese male Zucker rats were used. Serum levels of hepatic enzymes and TNF-alpha were quantified. Hepatic oxidative stress (ROS, TBARS and GSH content) and MMP-2 and MMP-9 (protein expression and activity) were evaluated. Liver fatty acid profiling, performed by GC-MS, was used for the quantification of desaturase activities. Higher D5D and D9-16D were found in Obese Zucker rats as well as an increase in D9-18D in MCD rats. D6D was found only in MCD rats. A negative correlation between D5D and D9-16D versus TBARS, ROS and TNF-alpha and a positive correlation with GSH were shown in fatty livers besides a positive correlation between D9-18D versus TBARS, ROS and TNF-alpha and a negative correlation with GSH. A positive correlation between D5D or D9-16D or D9-18D versus protein expression and the activity of MMP-2 were found. NAFLD animal models showed comparable serum enzymes. These results reinforce and extend findings on the identification of therapeutic targets able to counteract NAFLD disorder.

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Section: Resultssupporting

confidence: 88%

Fatty Acid Desaturase Involvement in Non-Alcoholic Fatty Liver Disease Rat Models: Oxidative Stress Versus Metalloproteinases

Palladini

Pasqua²,

Berardo³

et al. 2019

Nutrients

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“…It has been reported that leptin inhibits the production of triacylglycerol [45], whereas insulin promotes it [46,47]. In obese Zucker rats (fa/fa), approximately 2 to 4 times more triacylglycerol than in lean rats (+/+ or fa/+) was accumulated in the liver, followed by its secretion into circulation [48]. Since the leptin receptor did not function in the fatty rats, the turnover of triacylglycerol was more active in the synthesis than in the degradation by the action of insulin.…”

Section: Discussionmentioning

confidence: 99%

Coenzyme A and Its Thioester Pools in Obese Zucker and Zucker Diabetic Fatty Rats

et al. 2020

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Feeding behavior is closely related to hypothalamic malonyl-CoA level in the brain and diet-induced obesity affects total CoA pools in liver. Herein, we performed a comprehensive analysis of the CoA pools formed in thirteen tissues of Zucker and Zucker diabetic fatty (ZDF) rats. Hypothalamic malonyl-CoA levels in obese rats remained low and were almost the same as those of lean rats, despite obese rats having much higher content of leptin, insulin, and glucose in their sera. Regardless of the fa-genotypes, larger total CoA pools were formed in the livers of ZDF rats and the size of hepatic total CoA pools in Zucker rats showed almost one tenth of the size of ZDF rats. The decreased total CoA pool sizes in Zucker rats was observed in the brown adipose tissues, while ZDF-fatty rats possessed 6% of total CoA pool in the lean rats in response to fa deficiency. This substantially lower CoA content in the obese rats would be disadvantageous to non-shivering thermogenesis. Thus, comparing the intracellular CoA behaviors between Zucker and ZDF rats, as well as the lean and fatty rats of each strain would help to elucidate features of obesity and type 2 diabetes in combination with result (s) of differential gene expression analysis and/or comparative genomics.

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“…24,25 Consequently, a dramatic decrease in leptin signaling results in hyperphagia, prominent central obesity, hyperinsulinemia, hyperlipidemia, and spontaneous severe hepatic steatosis, evident as early as 3 weeks of age. 26 –28 In contrast, ZL ( Fa/− ) rats do not develop hyperphagia, obesity nor hyperglycemia, 29 and do not develop hepatic steatosis when fed a normal chow diet. Owing to this unique phenotype, the ZL rat lends itself as an appropriate test system for investigating liver injury in patients with asymptomatic NAFLD.…”

Section: Introductionmentioning

confidence: 98%

Zucker Lean Rats With Hepatic Steatosis Recapitulate Asymptomatic Metabolic Syndrome and Exhibit Greater Sensitivity to Drug-Induced Liver Injury Compared With Standard Nonclinical Sprague-Dawley Rat Model

et al. 2020

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Fatty liver disease is a potential risk factor for drug-induced liver injury (DILI). Despite advances in nonclinical in vitro and in vivo models to assess liver injury during drug development, the pharmaceutical industry is still plagued by idiosyncratic DILI. Here, we tested the hypothesis that certain features of asymptomatic metabolic syndrome (namely hepatic steatosis) increase the risk for DILI in certain phenotypes of the human population. Comparison of the Zucker Lean (ZL) and Zucker Fatty rats fed a high fat diet (HFD) revealed that HFD-fed ZL rats developed mild hepatic steatosis with compensatory hyperinsulinemia without increases in liver enzymes. We then challenged steatotic HFD-fed ZL rats and Sprague-Dawley (SD) rats fed normal chow, a nonclinical model widely used in the pharmaceutical industry, with acetaminophen overdose to induce liver injury. Observations in HFD-fed ZL rats included increased liver injury enzymes and greater incidence and severity of hepatic necrosis compared with similarly treated SD rats. The HFD-fed ZL rats also had disproportionately higher hepatic drug accumulation, which was linked with abnormal hepatocellular efflux transporter distribution. Here, we identify ZL rats with HFD-induced hepatic steatosis as a more sensitive nonclinical in vivo test system for modeling DILI compared with SD rats fed normal chow.

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Heterozygosity for leptin receptor (fa) accelerates hepatic triglyceride accumulation without hyperphagia in Zucker rats

Cited by 6 publications

References 20 publications

Fatty Acid Desaturase Involvement in Non-Alcoholic Fatty Liver Disease Rat Models: Oxidative Stress Versus Metalloproteinases

Fatty Acid Desaturase Involvement in Non-Alcoholic Fatty Liver Disease Rat Models: Oxidative Stress Versus Metalloproteinases

Coenzyme A and Its Thioester Pools in Obese Zucker and Zucker Diabetic Fatty Rats

Zucker Lean Rats With Hepatic Steatosis Recapitulate Asymptomatic Metabolic Syndrome and Exhibit Greater Sensitivity to Drug-Induced Liver Injury Compared With Standard Nonclinical Sprague-Dawley Rat Model

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