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Medium-chain triglyceride supplementation under a low-carbohydrate formula is a promising therapy for adult-onset type II citrullinemia ☆

View Article: PubMed Central - PubMed

ABSTRACT

Background: Citrin, encoded by SLC25A13, is a component of the malate-aspartate shuttle, which is the main NADH-transporting system in the liver. Citrin deficiency causes neonatal intrahepatic cholestasis (NICCD), which usually resolves within the first year of life. However, small numbers of adults with citrin deficiency develop hyperammonemic encephalopathy, adult-onset type II citrullinemia (CTLN2), which leads to death due to cerebral edema. Liver transplantation is the only definitive therapy for patients with CTLN2. We previously reported that a lactose (galactose)-restricted and medium-chain triglyceride (MCT)-supplemented formula is notably effective for patients with NICCD. Citrin deficiency may impair the glycolysis in hepatocytes because of an increase in the cytosolic NADH/NAD+ ratio, leading to an energy shortage. MCT administration can provide energy to hepatocytes and was expected to have a good effect on CTLN2.

Methods: An MCT supplementation therapy under a low-carbohydrate formula was administered to five patients with CTLN2. Four of the patients had episodes of hyperammonemic encephalopathy, and one patient had postprandial hyperammonemia with no symptoms.

Results: One of the patients displaying hyperammonemic encephalopathy completely recovered with all normal laboratory findings. Others notably improved in terms of clinical and or laboratory findings with no hyperammonemic symptoms; however, the patients displayed persistent mild citrullinemia and occasionally had postprandial mild hyperammonemia most likely due to an irreversible change in the liver.

Conclusions: An MCT supplement can provide energy to hepatocytes and promote hepatic lipogenesis, leading to a reduction in the cytosolic NADH/NAD+ ratio. MCT supplementation under a low-carbohydrate formula could be a promising therapy for CTLN2 and should also be used to prevent CTLN2 to avoid irreversible liver damage.

No MeSH data available.


a: Glucose metabolism in citrin deficiency.b: Treatment with medium-chain triglycerides and hepatic lipogenesis.Abbreviations: Asp, aspartate; CiC, citrate carrier; cyt, cytosol; DHAP, dihydroxyacetone phosphate; Glc, glucose; GP, glycerol 3-phosphate: Mal, malate; mit, mitochondria; MCFA, medium-chain free fatty acid; NAD+, nicotinamide adenine dinucleotide; NADH, reduced nicotinamide adenine dinucleotide; NADP, nicotinamide adenine dinucleotide phosphate; NADPH, reduced nicotinamide adenine dinucleotide phosphate; OAA, oxaloacetate; PyC, pyruvate carrier; and Pyr, pyruvate.
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f0015: a: Glucose metabolism in citrin deficiency.b: Treatment with medium-chain triglycerides and hepatic lipogenesis.Abbreviations: Asp, aspartate; CiC, citrate carrier; cyt, cytosol; DHAP, dihydroxyacetone phosphate; Glc, glucose; GP, glycerol 3-phosphate: Mal, malate; mit, mitochondria; MCFA, medium-chain free fatty acid; NAD+, nicotinamide adenine dinucleotide; NADH, reduced nicotinamide adenine dinucleotide; NADP, nicotinamide adenine dinucleotide phosphate; NADPH, reduced nicotinamide adenine dinucleotide phosphate; OAA, oxaloacetate; PyC, pyruvate carrier; and Pyr, pyruvate.

Mentions: Citrin deficiency likely results in impairment of glycolysis due to an increased NADH/NAD+ ratio in cytosol (Fig. 3a). At a normal circumstance, the liver takes up a relatively fixed amount of fatty acids regardless of dietary intake and uses as a major energy source. Glucose uptake by hepatocytes is most likely limited to the postprandial period because of the low affinity of glucose transporter 2 and glucokinase for glucose. Glucose is not a major energy source for hepatocytes but is used for lipogenesis for generating ATP, acetyl-CoA and NADPH. Thus, the patients with citrin deficiency most likely have impairments in hepatic lipogenesis and cannot export and reserve fatty acids in their tissues. Characteristic low BMI in patients with CTLN2 may reflect these metabolic impairments [1].


Medium-chain triglyceride supplementation under a low-carbohydrate formula is a promising therapy for adult-onset type II citrullinemia ☆
a: Glucose metabolism in citrin deficiency.b: Treatment with medium-chain triglycerides and hepatic lipogenesis.Abbreviations: Asp, aspartate; CiC, citrate carrier; cyt, cytosol; DHAP, dihydroxyacetone phosphate; Glc, glucose; GP, glycerol 3-phosphate: Mal, malate; mit, mitochondria; MCFA, medium-chain free fatty acid; NAD+, nicotinamide adenine dinucleotide; NADH, reduced nicotinamide adenine dinucleotide; NADP, nicotinamide adenine dinucleotide phosphate; NADPH, reduced nicotinamide adenine dinucleotide phosphate; OAA, oxaloacetate; PyC, pyruvate carrier; and Pyr, pyruvate.
© Copyright Policy - CC BY-NC-ND
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC5121258&req=5

f0015: a: Glucose metabolism in citrin deficiency.b: Treatment with medium-chain triglycerides and hepatic lipogenesis.Abbreviations: Asp, aspartate; CiC, citrate carrier; cyt, cytosol; DHAP, dihydroxyacetone phosphate; Glc, glucose; GP, glycerol 3-phosphate: Mal, malate; mit, mitochondria; MCFA, medium-chain free fatty acid; NAD+, nicotinamide adenine dinucleotide; NADH, reduced nicotinamide adenine dinucleotide; NADP, nicotinamide adenine dinucleotide phosphate; NADPH, reduced nicotinamide adenine dinucleotide phosphate; OAA, oxaloacetate; PyC, pyruvate carrier; and Pyr, pyruvate.
Mentions: Citrin deficiency likely results in impairment of glycolysis due to an increased NADH/NAD+ ratio in cytosol (Fig. 3a). At a normal circumstance, the liver takes up a relatively fixed amount of fatty acids regardless of dietary intake and uses as a major energy source. Glucose uptake by hepatocytes is most likely limited to the postprandial period because of the low affinity of glucose transporter 2 and glucokinase for glucose. Glucose is not a major energy source for hepatocytes but is used for lipogenesis for generating ATP, acetyl-CoA and NADPH. Thus, the patients with citrin deficiency most likely have impairments in hepatic lipogenesis and cannot export and reserve fatty acids in their tissues. Characteristic low BMI in patients with CTLN2 may reflect these metabolic impairments [1].

View Article: PubMed Central - PubMed

ABSTRACT

Background: Citrin, encoded by SLC25A13, is a component of the malate-aspartate shuttle, which is the main NADH-transporting system in the liver. Citrin deficiency causes neonatal intrahepatic cholestasis (NICCD), which usually resolves within the first year of life. However, small numbers of adults with citrin deficiency develop hyperammonemic encephalopathy, adult-onset type II citrullinemia (CTLN2), which leads to death due to cerebral edema. Liver transplantation is the only definitive therapy for patients with CTLN2. We previously reported that a lactose (galactose)-restricted and medium-chain triglyceride (MCT)-supplemented formula is notably effective for patients with NICCD. Citrin deficiency may impair the glycolysis in hepatocytes because of an increase in the cytosolic NADH/NAD+ ratio, leading to an energy shortage. MCT administration can provide energy to hepatocytes and was expected to have a good effect on CTLN2.

Methods: An MCT supplementation therapy under a low-carbohydrate formula was administered to five patients with CTLN2. Four of the patients had episodes of hyperammonemic encephalopathy, and one patient had postprandial hyperammonemia with no symptoms.

Results: One of the patients displaying hyperammonemic encephalopathy completely recovered with all normal laboratory findings. Others notably improved in terms of clinical and or laboratory findings with no hyperammonemic symptoms; however, the patients displayed persistent mild citrullinemia and occasionally had postprandial mild hyperammonemia most likely due to an irreversible change in the liver.

Conclusions: An MCT supplement can provide energy to hepatocytes and promote hepatic lipogenesis, leading to a reduction in the cytosolic NADH/NAD+ ratio. MCT supplementation under a low-carbohydrate formula could be a promising therapy for CTLN2 and should also be used to prevent CTLN2 to avoid irreversible liver damage.

No MeSH data available.