• Journal of The Korean Society of Inherited Metabolic disease
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• v.22 no.1
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• pp.1-8
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• 2022

Long-chain fatty acid oxidation disorders (LC-FAOD) are an autosomal recessive inherited rare disease group that result in an acute metabolic crisis and chronic energy deficiency owing to the deficiency in an enzyme that converts long-chain fatty acids into energy. LC-FAOD includes carnitine palmitoyltransferase type 1 (CPT1), carnitine-acylcarnitine translocase (CACT), carnitine palmitoyltransferase type 2 (CPT2), very long-chain acyl-CoA dehydrogenase (VLCAD), long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD), and trifunctional protein (TFP) deficiencies. Common symptoms of LC-FAOD are hypoketotic hypoglycemia, cardiomyopathy, and myopathy. Depending on symptom onset, the disease can be divided as neonatal period, late infancy and early childhood, adolescence, or adult onset, but symptoms can appear at any time. The neonatal screening test (NBS) can be used to identify the characteristic plasma acylcarnitine profiles for each disease and confirmed by deficient enzyme analysis or molecular testing. Before introduction of NBS, the mortality rate of LC-FAOD was very high. With NBS implementation as routine neonatal care, the mortality rate was dramatically decreased, but severe symptoms such as rhabdomyolysis recur frequently and affect the quality of life. Triheptanoin (Dojolvi^®), the first drug for pediatric and adult patients with molecularly confirmed LC-FAOD, has recently been approved by the US Food and Drug Administration in 2020. In this review, the diagnosis of LC-FAOD and treatment including triheptanoin are summarized.

• Animal Bioscience
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• v.35 no.8
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• pp.1184-1194
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• 2022

Objective: High concentrate diets are widely used to satisfy high-yielding dairy cows; however, long-term feeding of high concentrate diets can cause subacute ruminal acidosis (SARA). The endocrine disturbance is one of the important reasons for metabolic disorders caused by SARA. However, there is no current report about thyroid hormones involved in liver metabolic disorders induced by a high concentrate diet. Methods: In this study, 12 mid-lactating dairy cows were randomly assigned to HC (high concentrate) group (60% concentrate of dry matter, n = 6) and LC (low concentrate) group (40% concentrate of dry matter, n = 6). All cows were slaughtered on the 21st day, and the samples of blood and liver were collected to analyze the blood biochemistry, histological changes, thyroid hormones, and the expression of genes and proteins. Results: Compared with LC group, HC group showed decreased serum triglyceride, free fatty acid, total cholesterol, low-density lipoprotein cholesterol, increased hepatic glycogen, and glucose. For glucose metabolism, the gene and protein expression of glucose-6-phosphatase and phosphoenolpyruvate carboxykinase 1 in the liver were significantly up-regulated in HC group. For lipid metabolism, the expression of sterol regulatory element-binding protein 1, long-chain acyl-CoA synthetase 1, and fatty acid synthase in the liver was decreased in HC group, whereas carnitine palmitoyltransferase 1α and peroxisome proliferator activated receptor α were increased. Serum triiodothyronine, thyroxin, free triiodothyronine (FT3), and hepatic FT3 increased in HC group, accompanied by increased expression of thyroid hormone receptor (THR) in the liver. Conclusion: Taken together, thyroid hormones may increase hepatic gluconeogenesis, β-oxidation and reduce fatty acid synthesis through the THR pathway to participate in the metabolic disorders caused by a high concentrate diet.

• Molecules and Cells
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• v.44 no.9
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• pp.637-646
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• 2021

Free fatty acids are converted to acyl-CoA by long-chain acyl-CoA synthetases (ACSLs) before entering into metabolic pathways for lipid biosynthesis or degradation. ACSL family members have highly conserved amino acid sequences except for their N-terminal regions. Several reports have shown that ACSL1, among the ACSLs, is located in mitochondria and mainly leads fatty acids to the β-oxidation pathway in various cell types. In this study, we investigated how ACSL1 was localized in mitochondria and whether ACSL1 overexpression affected fatty acid oxidation (FAO) rates in C2C12 myotubes. We generated an ACSL1 mutant in which the N-terminal 100 amino acids were deleted and compared its localization and function with those of the ACSL1 wild type. We found that ACSL1 adjoined the outer membrane of mitochondria through interaction of its N-terminal region with carnitine palmitoyltransferase-1b (CPT1b) in C2C12 myotubes. In addition, overexpressed ACSL1, but not the ACSL1 mutant, increased FAO, and ameliorated palmitate-induced insulin resistance in C2C12 myotubes. These results suggested that targeting of ACSL1 to mitochondria is essential in increasing FAO in myotubes, which can reduce insulin resistance in obesity and related metabolic disorders.

• Journal of The Korean Society of Inherited Metabolic disease
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• v.19 no.1
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• pp.20-25
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• 2019

Very-long-chain acyl-CoA dehydrogenase (VLCAD) deficiency (OMIM#201475) is an autosomal recessively inherited metabolic disorder of mitochondrial long-chain fatty acid oxidation. The clinical features of VLCAD deficiency is classified by three clinical forms according to the severity. Here, we report a case of later-onset episodic myopathic form of VLCAD deficiency whose diagnosis was confirmed by plasma acylcarnitine analysis and" multigene panel multigene panel sequencing. A 34-year old female patient visited genetics clinic for genetic evaluation for history of recurrent myopathy with intermittent rhabdomyolysis. She suffered first episode of rhabdomyolysis with acute renal failure requiring hemodialysis at twelve years old. After then, she suffered several times of recurrent rhabdomyolysis provoked by prolonged exercise or fasting. Physical and neurologic exam was normal. Serum AST/ALT and creatinine kinase (CK) levels were mildly elevated. However, according to her previous medical records, her AST/ALT, CK were highly elevated when she had rhabdomyolysis. In suspicion of fatty acid oxidation disorder, multigene panel sequencing and plasma acylcarnitine analysis were performed in non-fasting, asymptomatic condition for the differential diagnosis. Plasma acylcarnitine analysis revealed elevated levels of C14:1 ($1.453{\mu}mol/L$; reference, 0.044-0.285), and C14:2 ($0.323{\mu}mol/L$; 0.032-0.301) and upper normal level of C14 ($0.841{\mu}mol/L$; 0.065 -0.920). Two heterozygous mutation in ACADVL were detected by multigene panel sequencing and confirmed by Sanger sequencing: c.[1202G>A(;) 1349G>A] (p.[(Ser 401Asn)(;)(Arg450His)]). Diagnosis of VLCAD deficiency was confirmed and frequent meal with low-fat diet was educated for preventing acute metabolic derangement. Fatty acid oxidation disorders have diagnostic challenges due to their intermittent clinical and laboratorial presentations, especially in milder late-onset forms. We suggest that multigene panel sequencing could be a useful diagnostic tool for the genetically and clinically heterogeneous fatty acid oxidation disorders.