• 대한유전성대사질환학회지
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• 제22권1호
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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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• 제35권8호
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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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• 제44권9호
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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.

• 대한유전성대사질환학회지
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• 제19권1호
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• pp.20-25
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• 2019

Very-long-chain acyl-CoA dehydrogenase (VLCAD) 결핍증은 상염색체 열성으로 유전되는 유전성대사질환으로 미토콘드리아에서 장쇄지방산의 산화 장애이다. VLCAD 결핍증의 임상증상은 중증도 및 발현 시기에 따라 심각한 심장 이상을 동반하는 신생아기 발현형, 소아기 발현형, 지발형의 세 가지로 분류할 수 있다. 저자들은 혈장 아실카르니틴 분석과 유전자패널 염기서열분석 방법으로 확진된 성인기 발현형 VLCAD 결핍증 1례를 경험하였기에 보고하고자 한다. 34세 여자가 반복되는 근육통증과 간헐적 횡문근융해증의 병력을 주소로 내원하였다. 환자는 12세에 처음으로 운동 후 횡문근융해증으로 급성 신부전이 발생하여 혈액 투석을 받고 회복하였다. 이후 환자는 장시간의 운동이나 금식 후에 반복적으로 근육통증과 횡문근융해증이 발생하였다. 내원 시 신체 검진과 신경학적 검진은 정상이었다. 내원시 혈장 AST/ALT, Creatinine kinase (CK)는 약간 상승해있었으나, 이전 의무기록에 의하면 횡문근융해증이 있을 당시 AST/ALT, CK는 매우 상승하였다. 환자의 병력을 토대로 지방산대사장애 의심하에 감별진단을 위하여, 유전자 패널 염기서열 분석과 혈장 아실카르니틴 분석을 시행하였다. 혈장 아실카르니틴 분석결과 C14:1 ($1.453{\mu}mol/L$; 참고치, 0.044-0.285)와 C14:2 ($0.323{\mu}mol/L$; 0.032-0.301)가 증가였고, C14 ($0.841{\mu}mol/L$; 0.065-0.920)는 높은 정상이었다. 유전자패널 염기서열분석에서는 ACADVL 유전자에서 두 개의 병원성변이가 이형접합으로 발견되었으며, 이는 Sanger 염기서열 분석으로 확진되었다: c.[1202G>A(;)1349G>A] (p.[(Ser401Asn)(;)(Arg 450His)]). 환자는 생화학적, 유전학적 검사결과를 바탕으로 지발형 VLCAD 결핍증으로 확진되어 저지방식이와 급성 대사장애를 예방하기 위한 영양 교육을 받았다. 경증의 지발형 지방산 대사장애는 임상증상과 생화학적 검사 이상이 간헐적으로 발생하기 때문에 진단이 어렵다. 유전자패널 염기서열 분석은 지방산대사 장애와 같이 임상증상과 원인 유전자 이상이 다양한 대사 이상질환에서 유용한 진단법이 될 수 있다.