Reduced Carnitine Level Causes Death from Hypoglycemia: Possible Involvement of Suppression of Hypothalamic Orexin Expression During Weaning Period

Kuwajima, Masamichi; Fujihara, Hiroaki; Séi, Hiroyoshi; Umehara, Asako; Sei, Masako; Tsuda, Tatsuya; Sukeno, Akiko; Okamoto, Tatsuya; Inubushi, A.; Ueta, Yoichi; Doi, Toshio; Kido, Hiroshi

doi:10.1507/endocrj.k07-044

Cited by 21 publications

(21 citation statements)

References 45 publications

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“…Livers were cut into pieces and fixed in 10% formalin for histological analysis, or fresh-frozen in liquid nitrogen and stored at −80°C in a freezer until use. L-carnitine and α-tocopherol concentrations were decided based on previous reports, and were confirmed to show the same improvement in histological activity and stage in our STAM mouse model [13], [14].…”

Section: Methodssupporting

confidence: 81%

L-Carnitine Prevents Progression of Non-Alcoholic Steatohepatitis in a Mouse Model with Upregulation of Mitochondrial Pathway

et al. 2014

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Non-alcoholic steatohepatitis (NASH) is a severe form of non-alcoholic fatty liver disease characterized by lobular inflammation, hepatocellular ballooning, and fibrosis with an inherent risk for progression to cirrhosis and hepatocellular carcinoma (HCC). Mitochondrial dysfunction appears to play a role in the progression from simple steatosis to NASH. L-carnitine (L-b-hydroxy-g-N-trimethylaminobutyric acid), an essential nutrient that converts fat into energy in mitochondria, has been shown to ameliorate liver damage. The aim of the present study was to explore the preventive and therapeutic effect of L-carnitine in NASH model mice. Eight-week-old male STAM mice, a NASH-cirrhosis-hepatocarcinogenic model, were divided into 3 experimental groups and fed as follows: 1) high-fat diet (HFD) (control group); 2) HFD mixed with 0.28% L-carnitine (L-carnitine group); and 3) HFD mixed with 0.01% α-tocopherol (α-tocopherol group). After 4 or 8 weeks, mice were sacrificed. Blood samples and livers were collected, and hepatic tumors were counted and measured. Livers were subjected to histological study, immunohistochemical staining of 4-hydroxynonenal and ferritin, determination of 8-OHdG levels, mRNA and protein expressions for multiple genes, and metabolomic analysis. The intestinal microbiome was also analyzed. L-carnitine increased hepatic expression of genes related to long-chain fatty acid transport, mitochondrial β-oxidation, and antioxidant enzymes following suppression of hepatic oxidative stress markers and inflammatory cytokines in NASH, and mice treated with L-carnitine developed fewer liver tumors. Although α-tocopherol resulted in NASH improvement in the same manner as L-carnitine, it increased periodontitis-related microbiotic changes and hepatic iron transport-related gene expression and led to less effective for anti-hepatocarcinogenesis.ConclusionL-carnitine prevents progression of non-alcoholic steatohepatitis in a mouse model by upregulating the mitochondrial β-oxidation and redox system.

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Section: Methodssupporting

confidence: 81%

L-Carnitine Prevents Progression of Non-Alcoholic Steatohepatitis in a Mouse Model with Upregulation of Mitochondrial Pathway

et al. 2014

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“…These phenotypes in the fasted jvs −/− mice are similar to those in mouse models of narcolepsy [9], [20]. In these mice, a significant reduction in the number of c-Fos-positive orexin neurons, hypothalamic prepro-orexin mRNA expression, and orexin-A concentration in the cerebrospinal fluid (CSF) was observed [19], [21]. These findings indicate that the acylcarnitine availability is essential for normal sleep regulation and orexin cell functions.…”

Section: Introductionsupporting

confidence: 57%

Effects of Oral L-Carnitine Administration in Narcolepsy Patients: A Randomized, Double-Blind, Cross-Over and Placebo-Controlled Trial

Miyagawa

Kawamura²,

Obuchi³

et al. 2013

PLoS ONE

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Narcolepsy is a sleep disorder characterized by excessive daytime sleepiness, cataplexy, and rapid eye movement (REM) sleep abnormalities. A genome-wide association study (GWAS) identified a novel narcolepsy-related single nucleotide polymorphism (SNP), which is located adjacent to the carnitine palmitoyltransferase 1B (CPT1B) gene encoding an enzyme involved in β-oxidation of long-chain fatty acids. The mRNA expression levels of CPT1B were associated with this SNP. In addition, we recently reported that acylcarnitine levels were abnormally low in narcolepsy patients. To assess the efficacy of oral l-carnitine for the treatment of narcolepsy, we performed a clinical trial administering l-carnitine (510 mg/day) to patients with the disease. The study design was a randomized, double-blind, cross-over and placebo-controlled trial. Thirty narcolepsy patients were enrolled in our study. Two patients were withdrawn and 28 patients were included in the statistical analysis (15 males and 13 females, all with HLA-DQB1*06:02). l-carnitine treatment significantly improved the total time for dozing off during the daytime, calculated from the sleep logs, compared with that of placebo-treated periods. l-carnitine efficiently increased serum acylcarnitine levels, and reduced serum triglycerides concentration. Differences in the Japanese version of the Epworth Sleepiness Scale (ESS) and the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36) vitality and mental health subscales did not reach statistical significance between l-carnitine and placebo. This study suggests that oral l-carnitine can be effective in reducing excessive daytime sleepiness in narcolepsy patients.Trial RegistrationUniversity hospital Medical Information Network (UMIN) UMIN000003760

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“…Evidence suggests that exposure to recurrent hypoglycaemia causes functional adaptation in orexin-A containing neurons [55,56]. These neurons mediate motorneuronal excitability of the upper airway muscle in a glutamate dependent manner [57], and arousal through the noradrenergic neuronal system [58].…”

Section: Hypoglycaemia Causes Osa: the Role Of Orexinergic Mechanismmentioning

confidence: 99%

The Mechanism of Dead-in-Bed Syndrome and Other Sudden Unexplained Nocturnal Deaths

Parekh¹

2009

CDR

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The mechanism of dead-in-bed syndrome (DBS), a rare but devastating condition that mainly affects young type 1 diabetes patients, remains mysterious. A new theory is proposed to explain this syndrome. This theory suggests that repeated episodes of hypoglycaemia-induced adaptation in orexin-A neurons cause (i) defective awakening and (ii) hypotonia of upper airway muscles during sleep. Consequently, due to the combined effect of these factors, long-term exposure of intermittent hypoxia occurs, leading to a combination of factors - such as depression of ventilation, increase in sympathetic tone, fluctuations in intrathoracic pressure and cardiac arrhythmias - these in conjunction with an underlying cardiovascular pathology (genetically inherited or acquired) cause cardio-respiratory failure and thus sudden death during sleep. This mechanism can be generalized to explain other cases of sudden unexplained nocturnal deaths including sudden infant deaths (SIDs).

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Reduced Carnitine Level Causes Death from Hypoglycemia: Possible Involvement of Suppression of Hypothalamic Orexin Expression During Weaning Period

Cited by 21 publications

References 45 publications

L-Carnitine Prevents Progression of Non-Alcoholic Steatohepatitis in a Mouse Model with Upregulation of Mitochondrial Pathway

L-Carnitine Prevents Progression of Non-Alcoholic Steatohepatitis in a Mouse Model with Upregulation of Mitochondrial Pathway

Effects of Oral L-Carnitine Administration in Narcolepsy Patients: A Randomized, Double-Blind, Cross-Over and Placebo-Controlled Trial

The Mechanism of Dead-in-Bed Syndrome and Other Sudden Unexplained Nocturnal Deaths

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