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Open Access

Acylcarnitines: Nomenclature, Biomarkers, Therapeutic Potential, Drug Targets, and Clinical Trials

Maija Dambrova, Marina Makrecka-Kuka, Janis Kuka, Reinis Vilskersts, Didi Nordberg, Misty M. Attwood, Stefan Smesny, Zumrut Duygu Sen, An Chi Guo, Eponine Oler, Siyang Tian, Jiamin Zheng, David S. Wishart, Edgars Liepinsh and Helgi B. Schiöth
Jukka Hakkola, ASSOCIATE EDITOR
Pharmacological Reviews July 2022, 74 (3) 506-551; DOI: https://doi.org/10.1124/pharmrev.121.000408

Article Figures & Data

Figures

  • Figure
  • Fig. 1
    Fig. 1

    Acyl-chain categories and respective numbers of acylcarnitines in each category. The size of each mitochondrion depicts the relative abundance of short-, medium-, long- and very long-chain acylcarnitines.

  • Fig. 2
    Fig. 2

    Representative structures of various acylcarnitine classes.

  • Fig. 3
    Fig. 3

    Generalized model of acylcarnitine synthesis, transport and metabolism in (A) peroxisomes and (B) mitochondria. Acylcarnitines are generated in the mitochondria and peroxisomes of various tissues. BC, branched chain; FATP1, long-chain fatty acid transport protein 1; LC, long chain; MC, medium chain; MITO, mitochondria; mt-β-ox, mitochondrial fatty acid β-oxidation; PEX, peroxisomes; pex-α/β-ox, peroxisomal fatty acid α- or β-oxidation; TCA cycle, tricarboxylic acid cycle; VLC, very long-chain.

  • Fig. 4
    Fig. 4

    Enzyme and transporter preferences for acylcarnitines of various chain lengths (C2–C23). Shading represents the enzyme/transporter preference for specific acylcarnitine lengths. Based on the literature data, a darker area indicates a higher preference for a specific acylcarnitine, whereas a lighter area indicates a lower preference for a specific acylcarnitine or limited data availability.

  • Fig. 5
    Fig. 5

    Enzymes, transporters and signaling pathways as potential targets to decrease the acylcarnitine content. Arrows indicate enzymatic reaction or transport; T-shaped arrows indicate inhibition. The interrupted arrow indicates indirect activation by the PI3K/Akt signaling pathway. FA, fatty acids; FATP1, long-chain fatty acid transport protein 1; IRS, insulin receptor substrate; LC, long chain; mt-β-ox, mitochondrial fatty acid β oxidation; PI3K, phosphoinositide 3-kinase; TCA cycle, tricarboxylic acid cycle.

  • Fig. 6
    Fig. 6

    Enzymes and transporters related to the development of FAOD and the accumulation of acylcarnitines. Red arrows indicate reverse flux of acyl moieties and efflux of acylcarnitines. The main enzymes and transporters related to FAOD are marked in blue. ACAD9, acyl-CoA dehydrogenase family member 9; ECH, enoyl-CoA hydratase; ETFQO, electron transfer flavoprotein-ubiquinone oxidoreductase; LCKAT/MCKAT, long-/medium-chain 3-ketothiolase, MCHAD/SCHAD, medium-/short-chain 3-hydroxyacyl-CoA dehydrogenase.

  • Fig. 7
    Fig. 7

    Enzymes, ion channels, and (signaling) pathways affected by long-chain acylcarnitines in myocytes. Arrows indicate enzymatic reaction or transport; T-shaped arrows indicate inhibition. FA, fatty acids; FATP1, long-chain fatty acid transport protein 1; IRS, insulin receptor substrate; LC, long chain; mt-β-ox, mitochondrial fatty acid β oxidation; PDC, pyruvate dehydrogenase complex; TCA cycle, tricarboxylic acid cycle.

  • Fig. 8
    Fig. 8

    Clinical trials involving acylcarnitines and L-carnitine. We identified 64 trials using keyword searches with the term acylcarnitine in ClinicalTrials.gov and PubMed with the clinical trials filter. In addition, eight studies assessing L-carnitine (levocarnitine) were identified, but these studies are investigated separately in (D). The data were subsequently manually curated and classified into different categories, such as the type of clinical study, condition/diagnosis and drug classes. (A) Type of clinical study as defined in Clinical.Trials.gov with the number of clinical trials identified in each category. Study types included observational, procedural, nutritional supplementation (nutritional suppl.), behavioral interventions, nutritional diet interventions, and drug studies. Percent and number of clinical trials in parentheses. (B) Condition/diagnosis of the participants. The data show several deficiencies (grouped as Deficiency), such as carnitine deficiency, vitamin B6 deficiency, malnutrition, and infant nutrition disorders. Energy storage diseases include glucose transporter type 1 deficiency syndrome, glucose intolerance, and glycogen storage disease type V. Fatty acid oxidation disorders (FAODs) include long-chain fatty acid transport deficiency, carnitine palmitoyl transferase type 1A (CPT1A) deficiency, and trifunctional protein deficiency. The category “Other” represents polycystic ovary syndrome (PCOS), inborn errors of metabolism, sepsis, complications from premature birth, and Klinefelter syndrome. Type 2 diabetes (T2DM), insulin resistance (IR), and obesity are an often-combined study group in clinical trials and are thereby counted together as one category. Acidemias represent both propionic acidemia and methylmalonic acidemia. (C) Drug classes. The “Other” group includes drugs that act as analgesics, growth hormone receptor antagonists, hepatoprotectants, amino acid analogs, and antihypertensives. (D) Additionally, we identified 126 trials using keyword searches with the term levocarnitine in ClinicalTrials.gov. Conditions treated with levocarnitine with the number of studies in each category. Fertility-related disorders include polycystic ovary syndrome (PCOS) and male infertility. Type 2 diabetes (T2DM), glucose intolerance (GI), insulin resistance (IR), and obesity are an often-combined study group in clinical trials and are thereby counted together as one category. Cardiovascular disease (CVD) includes heart failure, vascular disease, atherosclerosis, heart septal defects, arterial disease, and coronary artery disease. Neuromuscular disorders include spinal muscular atrophy, sarcopenia, postpoliomyelitis syndrome, and muscle soreness. Infections are represented by sepsis and viral infections. In addition to these dominant conditions in the figure, there are three studies in the areas of neurodegenerative disorders, including progressive supranuclear palsy, Alzheimer’s disease, and multiple sclerosis. Neuropsychiatric disorders (three studies) include attention deficit hyperactivity disorder, bipolar disorder, and autism. Other studies were related to prematurity, thyroid-related disease, fatigue, ulcerative colitis, and toxicity (three studies each) and central nerve injury, carnitine-related deficiency, Sjogren’s syndrome, sleep apnea, thalassemia, chronic pancreatitis, migraine, and dyslipidemia (one study each).

Tables

  • TABLE 1

    Short-chain acylcarnitines and diseases with altered short-chain acylcarnitine levels in blood (serum, plasma, dried blood spots) or urine

    Acylcarnitine (Fatty Acid Moiety)SampleIncreased/ decreasedDisease with Altered Acylcarnitine Concentration
    Acetylcarnitine (C2:0)BloodIncreasedVery long-chain acyl-CoA dehydrogenase deficiency (Costa et al., 1997); colorectal cancer (Ni et al., 2014); short-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (Clayton et al., 2001); paclitaxel-induced neuropathy (Sun et al., 2018); type 2 diabetes (Adams et al., 2009; Mai et al., 2013; Ciborowski et al., 2015; Abu Bakar and Sarmidi, 2017); chronic heart failure (Ueland et al., 2013); ornithine transcarbamylase (Ohtani et al., 1988); prediabetes (Wang-Sattler et al., 2012; Mai et al., 2013); type 1 diabetes (Adal et al., 2006); methylmalonic acidemia (Minkler and Hoppel, 1993); myeloma (Steiner et al., 2018); diastolic heart failure (Zordoky et al., 2015)
    Decreased3-Methyl-crotonyl-glycinuria (Thomsen et al., 2015); antiviral drug induced neuropathy (Famularo et al., 1997; James, 1997); Alzheimer’s disease (Cristofano et al., 2016); major depressive disorder (Nasca et al., 2018); carnitine palmitoyltransferase 2 deficiency (Hori et al., 2010); familial Mediterranean fever (Kiykim et al., 2016); chronic fatigue syndrome (Kuratsune et al., 1998); methylmalonic acidemia (Vernez et al., 2004); hepatocellular carcinoma (Lu et al., 2016; Takaya et al., 2019); coronary artery disease (Shah et al., 2010)
    UrineIncreasedColorectal cancer (Ni et al., 2014); uterine fibroids (Wang et al., 2020); heart failure (Matsui et al., 1994); diabetes (Dellow et al., 1999); hepatocellular carcinoma (Ladep et al., 2014)
    DecreasedCarnitine palmitoyltransferase 2 deficiency (Hori et al., 2010)
    Propionylcarnitine (C3:0)BloodIncreasedMethylmalonic academia/methylmalonyl-CoA mutase (Ghoraba et al., 2015; Han et al., 2015; Keyfi et al., 2019; Kang et al., 2020); propionic academia/mitochondrial propionyl-CoA carboxylase deficiency (Monostori et al., 2017; Curnock et al., 2020); obesity and type 2 diabetes (Libert et al., 2018); cobalamin C deficiency (Rahmandar et al., 2014); chronic heart failure (Ueland et al., 2013); diastolic heart failure (Zordoky et al., 2015); systolic heart failure (Zordoky et al., 2015)
    DecreasedFamilial Mediterranean fever (Kiykim et al., 2016); type 2 diabetes (Adams et al., 2009)
    UrineDecreasedObesity (Cho et al., 2017a)
    Butyrylcarnitine (C4:0)BloodIncreasedShort-chain acyl-CoA dehydrogenase (Dawson et al., 1995; Young et al., 2003; van Maldegem et al., 2006; 2010; Battisti et al., 2007; Forni et al., 2010; Gallant et al., 2012; Lampret et al., 2015; An et al., 2016; Tonin et al., 2016); glutaric aciduria 2 (Forni et al., 2010; Prasad and Hussain, 2015); heart failure (Cheng et al., 2015); ethylmalonic encephalopathy (Zafeiriou et al., 2007; Drousiotou et al., 2011); nonalcoholic fatty liver disease (Kalhan et al., 2011); obesity (Butte et al., 2015); systolic heart failure (Zordoky et al., 2015)
    DecreasedCeliac disease (Bene et al., 2005); acute cerebral infarction (Zhang et al., 2017b)
    UrineIncreasedShort-chain acyl-CoA dehydrogenase deficiency (Bhala et al., 1995); obesity (Cho et al., 2017a)
    Valerylcarnitine (C5:0)BloodIncreasedExudative age-related macular degeneration (Chao de la Barca et al., 2020); type 2 diabetes (Mihalik et al., 2010; Sun et al., 2020); obesity (Mihalik et al., 2010); acute cerebral infarction (Zhang et al., 2017b); diastolic heart failure (Zordoky et al., 2015); systolic heart failure (Zordoky et al., 2015)
    DecreasedPregnancy [(Bahado-Singh et al., 2014) – in serum of pregnant women with fetus with congenital heart defect]
  • TABLE 2

    Medium-chain acylcarnitines and diseases with altered medium-chain acylcarnitine levels in blood (serum, plasma, dried blood spots) or urine

    Acylcarnitine (Fatty Acid Moiety)SampleIncreased/ decreasedDisease with Altered Acylcarnitine Concentration
    Caproylcarnitine (C6:0)BloodIncreasedPsoriasis (Chen et al., 2021); cardiovascular diseases (Kukharenko et al., 2020); Norman-Roberts syndrome (Caksen et al., 2004); type 2 diabetes (Adams et al., 2009; Mihalik et al., 2010; Batchuluun et al., 2018); carnitine palmitoyltransferase 2 deficiency (Fontaine et al., 1998); familial Mediterranean fever (Kiykim et al., 2016); multiple acyl-CoA dehydrogenase deficiency (Saral et al., 2018); cardiovascular diseases in type 2 diabetes (Zhao et al., 2020); gestational diabetes (Batchuluun et al., 2018)
    DecreasedCeliac disease (Bene et al., 2005)
    UrineIncreasedMedium-chain acyl-CoA dehydrogenase deficiency (Bennett et al., 1990; Schmidt-Sommerfeld et al., 1992)
    Octanoylcarnitine (8:0)BloodIncreasedGlutaric aciduria 2 (Prasad and Hussain, 2015); ulcerative colitis (Kolho et al., 2017); Crohn’s disease (Kolho et al., 2017); medium-chain acyl-CoA dehydrogenase deficiency (Costa et al., 1997; Rhead, 2006; Khalid et al., 2010); multiple acyl-CoA dehydrogenase deficiency (Saral et al., 2018); exfoliation syndrome (Leruez et al., 2018); gestational diabetes (Batchuluun et al., 2018); type 2 diabetes (Adams et al., 2009; Mihalik et al., 2010; Batchuluun et al., 2018); cardiovascular diseases in type 2 diabetes (Zhao et al., 2020); cardioembolic stroke, its recurrence (Seo et al., 2018); diastolic heart failure (Zordoky et al., 2015)
    DecreasedCeliac disease (Bene et al., 2005); very long-chain acyl-CoA dehydrogenase deficiency (Costa et al., 1997); breast cancer (Park et al., 2019); hepatocellular carcinoma and liver cirrhosis (Kim et al., 2019); familial Mediterranean fever (Kiykim et al., 2016); human immunodeficiency virus (Waagsbo et al., 2016); pregnancy [(Bahado-Singh et al., 2014) – in serum of pregnant women with fetus with congenital heart defect]; coronary artery disease (Shah et al., 2010)
    UrineIncreasedMedium-chain acyl-CoA dehydrogenase deficiency (Duran et al., 1984; 1985; Tserng et al., 1990; Schmidt-Sommerfeld et al., 1992); obesity (Cho et al., 2017a); multiple acyl-CoA dehydrogenase deficiency (Sugiyama et al., 1990; Vallée et al., 1994); uterine fibroids (Wang et al., 2020)
    Nonanoylcarnitine (9:0)BloodDecreasedPsoriasis (Ottas et al., 2017; Chen et al., 2021); pregnancy [(Bahado-Singh et al., 2014) – in serum of pregnant women with fetus with congenital heart defect]
    UrineDecreasedObesity (Cho et al., 2017a)
    Decanoylcarnitine (C10:0)BloodIncreasedGlutaric aciduria 2 (Prasad and Hussain, 2015); ulcerative colitis (Kolho et al., 2017); Crohn’s disease (Kolho et al., 2017); obesity (Mihalik et al., 2010); medium-chain acyl-CoA dehydrogenase deficiency disorders (Woo et al., 2011); overweight (Kim et al., 2015); multiple acyl-CoA dehydrogenase deficiency (Schmidt-Sommerfeld et al., 1993; Saral et al., 2018); type 2 diabetes (Adams et al., 2009); age-related increase in alanine aminotransferase (Jung et al., 2014); prostate cancer (Zoni et al., 2019); Yin-deficiency-heat syndrome (Yi et al., 2020); cardiovascular diseases in type 2 diabetes (Zhao et al., 2020); cardioembolic stroke, its recurrence (Seo et al., 2018); diastolic heart failure (Zordoky et al., 2015)
    DecreasedCeliac disease (Bene et al., 2005); colorectal cancer (Tan et al., 2013); esophageal squamous cell carcinoma (Xu et al., 2013); inflammatory bowel disease (Danese et al., 2011); phenylketonuria (Weigel et al., 2008); intracerebral hemorrhage (Zhang et al., 2017b); pregnancy [(Bahado-Singh et al., 2014) – in serum of pregnant women with fetus with congenital heart defect]
    UrineIncreasedOverweight (Wang et al., 2011); renal cell carcinoma (Nizioł et al., 2018)
    Lauroylcarnitine (C12:0)BloodIncreasedVery long-chain acyl-CoA dehydrogenase deficiency (Costa et al., 1997); Yin deficiency (Yi et al., 2020); multiple acyl-CoA dehydrogenase deficiency (Saral et al., 2018); cardiovascular diseases in type 2 diabetes (Zhao et al., 2020); diastolic heart failure (Zordoky et al., 2015)
    DecreasedCeliac disease (Bene et al., 2005); psoriasis (Ottas et al., 2017); intracerebral hemorrhage (Zhang et al., 2017b); pregnancy [(Bahado-Singh et al., 2014) – in serum of pregnant women with fetus with congenital heart defect]
    UrineIncreasedRenal cell carcinoma (Nizioł et al., 2018)
  • TABLE 3

    Long-chain acylcarnitines and diseases with altered long-chain acylcarnitine levels in blood (serum, plasma, dried blood spots) or urine

    Acylcarnitine (Fatty Acid Moiety)SampleIncreased/ decreasedDisease with Altered Acylcarnitine Concentration
    Myristoylcarnitine (14:0)BloodIncreasedVery long-chain acyl-CoA dehydrogenase deficiency (Costa et al., 1997; Peng et al., 2013); carnitine/acylcarnitine translocase deficiency (Wasant et al., 2002); carnitine palmitoyl transferase 2 deficiency (Minkler et al., 2005); glutaric acidemia type 2 (Peng et al., 2013); sleep deprivation (Yoon et al., 2019); type 2 diabetes (Adams et al., 2009); cardiovascular diseases in type 2 diabetes (Zhao et al., 2020); cardiovascular mortality in chronic kidney disease (Kalim et al., 2013)
    DecreasedCeliac disease (Bene et al., 2005); chronic fatigue syndrome (Reuter and Evans, 2011)
    UrineIncreasedUterine fibroids (Wang et al., 2020)
    Palmitoylcarnitine (C16:0)BloodIncreasedVery long-chain acyl-CoA dehydrogenase deficiency (Costa et al., 1997); sleep deprivation (Yoon et al., 2019); carnitine palmitoyl transferase 2 deficiency (Minkler et al., 2005); carnitine/acylcarnitine translocase deficiency (Wasant et al., 2002); type 2 diabetes (Mihalik et al., 2010; Zhang et al., 2014; Qiu et al., 2016); nonalcoholic fatty liver disease (Chen et al., 2016); obesity (Mihalik et al., 2010); pulmonary arterial hypertension (Brittain et al., 2016); chronic heart failure (Ueland et al., 2013); cardiovascular mortality in chronic kidney disease (Kalim et al., 2013); diastolic heart failure (Zordoky et al., 2015; Hunter et al., 2016); systolic heart failure (Hunter et al., 2016); increased all-cause mortality and hospitalization in heart failure patients (Ahmad et al., 2016)
    DecreasedIntracerebral hemorrhage (Zhang et al., 2017b); carnitine palmitoyltransferase 1A deficiency (Fingerhut et al., 2001); psoriasis (Chen et al., 2021)
    FecesIncreasedCirrhosis (Huang et al., 2013)
    Stearoylcarnitine (C18:0)BloodIncreasedCarnitine/acylcarnitine translocase deficiency (Wasant et al., 2002); chronic fatigue syndrome (Reuter and Evans, 2011); pulmonary arterial hypertension (Brittain et al., 2016); carnitine palmitoyltransferase 2 deficiency (Minkler et al., 2005); cardiovascular mortality in chronic kidney disease (Kalim et al., 2013); diastolic heart failure (Hunter et al., 2016); systolic heart failure (Hunter et al., 2016)
    DecreasedIntracerebral hemorrhage (Zhang et al., 2017b); carnitine palmitoyltransferase 1A deficiency (Fingerhut et al., 2001)
  • TABLE 4

    Very long-chain acylcarnitines and diseases with altered very long-chain acylcarnitine levels in blood (serum, plasma, dried blood spots) or urine

    Acylcarnitine (Fatty Acid Moiety)SampleIncreased/ decreasedDisease with Altered Acylcarnitine Concentration (Reference)
    Behenoylcarnitine (C22:0)BloodDecreasedAcute cerebral infarction (Zhang et al., 2017b)
    UrineIncreasedZellweger syndrome (Duranti et al., 2008); infantile Refsum disease (Duranti et al., 2008); D-bifunctional protein deficiency (Duranti et al., 2008)
    Lignoceroylcarnitine (C24:0)BloodIncreasedType 2 diabetes (Zhang et al., 2014)
    DecreasedCardiovascular diseases in type 2 diabetes (Zhao et al., 2020)
    UrineIncreasedZellweger syndrome (Duranti et al., 2008); infantile Refsum disease (Duranti et al., 2008); type 2 diabetes (Zhang et al., 2014)
    Cerotoylcarnitine (C26:0)BloodIncreasedZellweger syndrome (Klouwer et al., 2017), X-linked adrenoleukodystrophy (van de Beek et al., 2016), cardiovascular mortality in chronic kidney disease (Kalim et al., 2013)
    UrineIncreasedZellweger syndrome (Duranti et al., 2008); infantile Refsum disease (Duranti et al., 2008)
  • TABLE 5

    Unsaturated-chain acylcarnitines and diseases with altered unsaturated-chain acylcarnitine levels in blood (serum, plasma, dried blood spots) or urine

    Acylcarnitine (Fatty Acid Moiety)SampleIncreased/ decreasedDisease with Altered Acylcarnitine Concentration
    Butenylcarnitine (C4:1)BloodIncreasedMaternal obesity/prepregnant obesity of mothers (Schlueter et al., 2020)
    Hexenoylcarnitine (C6:1)BloodIncreasedObesity in adolescence (Cho et al., 2017a)
    DecreasedAdolescent idiopathic scoliosis (Sun et al., 2016b)
    Decenoylcarnitine (C10:1)BloodIncreasedOverweight (Kang et al., 2018)
    DecreasedSchizophrenia (Cao et al., 2020); familial Mediterranean fever (Kiykim et al., 2016)
    Decadienoylcarnitine C10:2)BloodIncreased2,4-Dienoyl-CoA reductase deficiency (Roe et al., 1990; Kimura et al., 2004; Miinalainen et al., 2009)
    DecreasedFamilial Mediterranean fever (Kiykim et al., 2016); schizophrenia (Cao et al., 2020)
    Dodecenoylcarnitine (C12:1)BloodIncreasedMitochondrial dysfunction in diabetes patients (Abu Bakar and Sarmidi, 2017); childhood obesity (Wahl et al., 2012)
    DecreasedPlacental abruption (Gelaye et al., 2016) – increase in dodecanoylcarnitine/dodecenoylcarnitine ratio (C12/C12:1)
    Tetradecenoylcarnitine (C14:1)BloodIncreasedVery long-chain acyl-CoA dehydrogenase deficiency (Wood et al., 2001; Shigematsu et al., 2003; Tajima et al., 2008; Laforet et al., 2009; Hisahara et al., 2015; Lepori et al., 2018); trifunctional protein (mitochondrial long-chain ketoacyl-CoA thiolase) deficiency (Das et al., 2006); mitochondrial dysfunction in diabetes patients (Abu Bakar and Sarmidi, 2017); nonalcoholic fatty liver disease (Chen et al., 2016); insulin resistance, type 2 diabetes (Mai et al., 2013)
    Tetradecadienoylcarnitine (C14:2)BloodIncreasedInsulin resistance, type 2 diabetes (Mai et al., 2013) Alzheimer’s disease (Huo et al., 2020)
    Hexadecenoylcarnitine (C16:1)BloodIncreasedChildhood obesity (Wahl et al., 2012)
    DecreasedFamilial Mediterranean fever (Kiykim et al., 2016)
    Octadecenoylcarnitine (C18:1)BloodIncreasedCarnitine palmitoyltransferase 2 deficiency (Gempel et al., 2001; 2002; Minkler et al., 2005; Brucknerova et al., 2008; Illsinger et al., 2008; Tajima et al., 2017); cardiovascular mortality in incident dialysis patients (Kalim et al., 2013); schizophrenia (Cao et al., 2020); succinic semialdehyde dehydrogenase deficiency (Kirby et al., 2020); neonatal macrosomia (Wright and Baker, 2020); liver cirrhosis (Miyaaki et al., 2020); carnitine/acylcarnitine translocase deficiency (Iacobazzi et al., 2004); ischemia/reperfusion (Shah et al., 2012; Rizza et al., 2014); increased all-cause mortality and hospitalization in heart failure patients (Ahmad et al., 2016)
    Octadecadienylcarnitine (C18:2)BloodIncreasedParkinson’s disease (Chang et al., 2018); chronic heart failure (Ahmad et al., 2016; Hunter et al., 2016); carnitine/acylcarnitine translocase deficiency (Iacobazzi et al., 2004); ischemia/reperfusion (Shah et al., 2012; Rizza et al., 2014); increased all-cause mortality and hospitalization in heart failure patients (Ahmad et al., 2016)
  • TABLE 6

    Branched-chain acylcarnitines and diseases with altered branched-chain acylcarnitine levels in blood (serum, plasma, dried blood spots) or urine

    Acylcarnitine (Fatty Acid Moiety)SampleIncreased/ decreasedDisease with Altered Acylcarnitine Concentration
    Isobutyrylcarnitine (C4:0 M)BloodIncreasedIsobutyryl-CoA dehydrogenase deficiency (Forni et al., 2010); glutaric aciduria type 2 (Forni et al., 2010); ethylmalonic encephalopathy (Forni et al., 2010); gestational diabetes (Roy et al., 2018)
    DecreasedTraumatic brain injury (Jeter et al., 2013)
    UrineIncreasedGlutaric aciduria type 2 (Sugiyama et al., 1990); multiple acyl-CoA dehydrogenase deficiency (Kidouchi et al., 1988); acute coronary syndrome (Wang et al., 2018)
    Isovalerylcarnitine (C5:0 I)BloodIncreasedIsovaleric acidemia (Shigematsu et al., 2007; Forni et al., 2010; Couce et al., 2017; Lin et al., 2020); glutaric aciduria type 2 (Forni et al., 2010); 3-hydroxy-3-methylglutaryl-CoA lyase deficiency (Ma et al., 2011; Václavík et al., 2020); cardiovascular diseases (Kukharenko et al., 2020); acute kidney injury (Wan et al., 2019)
    DecreasedDaytime sleepiness (Pak et al., 2018); inflammatory bowel disease (Danese et al., 2011); ulcerative colitis (Bene et al., 2006); traumatic brain injury (Jeter et al., 2013)
    UrineIncreasedGlutaric aciduria type 2 (Shimizu et al., 1991); multiple acyl-CoA dehydrogenation deficiency (Kidouchi et al., 1988)
    2-Methylbutyrylcarnitine (C5:0 M)BloodIncreasedShort/branched-chain acyl-CoA dehydrogenase deficiency/2-methylbutyryl-CoA dehydrogenase deficiency (Madsen et al., 2006; Forni et al., 2010); glutaric aciduria type 2 (Forni et al., 2010); gout (Huang et al., 2020); nonalcoholic steatohepatitis (Kalhan et al., 2011)
    DecreasedPediatric obesity (Farook et al., 2015); traumatic brain injury (Jeter et al., 2013)
    Methylcrotonylcarnitine (C5:1 I)BloodIncreased3-methylcrotonyl-CoA carboxylase deficiency (van Hove et al., 1995); 3-hydroxy-3-methylglutaryl-CoA lyase deficiency (Václavík et al., 2020)
    Tiglylcarnitine (C5:1 M)BloodIncreasedBeta ketothiolase deficiency/acetyl-CoA acetyltransferase 1 gene mutation (Millington et al., 1987; Fukao et al., 2003; Wen et al., 2016); short-chain enoyl-CoA hydratase deficiency (Pajares et al., 2020)
    DecreasedFamilial Mediterranean fever (Kiykim et al., 2016); Lewis lung carcinoma (Wu et al., 2018); metabolic syndrome, type 2 diabetes, cardiovascular diseases (Yu et al., 2014)
    Pristanoyl-carnitineBloodIncreasedAlpha-methylacyl-CoA racemase deficiency (Herzog et al., 2017)
    Phytanoyl-carnitineBloodIncreasedRefsum disease (Herzog et al., 2017); rhizomelic chondrodysplasia punctata (Herzog et al., 2017)
  • TABLE 7

    Hydroxyl-/dicarboxyl‐chain acylcarnitines and diseases with altered hydroxyl-/dicarboxyl-chain acylcarnitine levels in blood (serum, plasma, dried blood spots) or urine

    Acylcarnitine (Fatty Acid Moiety)SampleIncreased/ decreasedDisease with Altered Acylcarnitine Concentration
    3-Hydroxy-propionylcarnitine (C3-OH)UrineDecreasedObesity (Cho et al., 2017a); systolic heart failure (Zordoky et al., 2015)
    Malonylcarnitine (C3-DC)BloodIncreasedMalonyl-CoA decarboxylase deficiency (Santer et al., 2003; Ficicioglu et al., 2005); propofol infusion syndrome (Wolf et al., 2001); short-chain enoyl-CoA hydratase mutation (Pajares et al., 2020); type 2 diabetes (Mai et al., 2013); methylmalonic acidemia (Maeda et al., 2007)
    DecreasedFamilial Mediterranean fever (Kiykim et al., 2016); cleft lip (Hozyasz et al., 2010); obesity (Libert et al., 2018); acute cerebral infarction (Zhang et al., 2017b)
    UrineIncreasedMalonyl-CoA decarboxylase deficiency (Yano et al., 1997); methylmalonic acidemia (Maeda et al., 2007)
    Methylmalonylcarnitine (C3:0 DC M)BloodIncreasedMethylmalonyl-CoA epimerase deficiency/methylmalonic acidemia (Maeda et al., 2007; Waters et al., 2016); familial Mediterranean fever (Kiykim et al., 2016); cobalamin C deficiency (Rahmandar et al., 2014)
    DecreasedMelanoma (Bayci et al., 2018); Intracerebral hemorrhage (Zhang et al., 2017b)
    UrineIncreasedMethylmalonyl-CoA epimerase deficiency/methylmalonic acidemia (Maeda et al., 2007; Waters et al., 2016)
    3-Hydroxybutyrylcarnitine (C4-OH)BloodIncreasedShort-chain L-3-hydroxyacyl-CoA dehydrogenase deficiency (Clayton et al., 2001; Hussain et al., 2005); prediabetes (Zhong et al., 2017); type 2 diabetes (Zhong et al., 2017); metallosis (Stepien et al., 2018); mitochondrial acetoacetyl-CoA thiolase deficiency (Catanzano et al., 2010); heart failure (Cheng et al., 2015)
    DecreasedPsoriasis (Chen et al., 2021)
    UrineIncreasedRenal cell carcinoma (Nizioł et al., 2018)
    Succinylcarnitine (C4-DC)BloodIncreasedSuccinyl-CoA ligase deficiency (Van Hove et al., 2010; Jaberi et al., 2013)
    Glutarylcarnitine (C5-DC)BloodIncreasedMultiple acyl-CoA dehydrogenase deficiency (Saral et al., 2018); glutaric acidemia type 1 (Couce Pico et al., 2008; Lee et al., 2013; Mohamed et al., 2015; Numata-Uematsu et al., 2017); renal insufficiency (Hennermann et al., 2009)
    DecreasedFamilial Mediterranean fever (Kiykim et al., 2016)
    UrineIncreasedMultiple acyl-CoA dehydrogenase deficiency (Sakuma et al., 1991); glutaric acidemia type 1 (Korman et al., 2007; Couce Pico et al., 2008; Kim et al., 2014)
    Methylglutarylcarnitine (C5-M-DC)BloodIncreased3-Hydroxy-3-methylglutaryl-CoA lyase deficiency (Roe et al., 1986; Santarelli et al., 2013; Václavík et al., 2020); acute kidney injury (Wan et al., 2019); pulmonary arterial hypertension (Mey et al., 2020)
    DecreasedTraumatic brain injury (Jeter et al., 2013); metabolic syndrome (Gong et al., 2020)
    UrineIncreased3-Methylglutaconic aciduria (Jooste et al., 1994); acute coronary syndrome (Wang et al., 2018)
    3-Hydroxyvalerylcarnitine (C5-OH)BloodIncreased3-Hydroxy-3-methylglutaryl-coenzyme A lyase deficiency (Grunert et al., 2017); holocarboxylase synthetase deficiency (Donti et al., 2016)
    DecreasedPsoriasis (Chen et al., 2021)
    3-Hydroxy-isovalerylcarnitine (C5-OH-I)BloodIncreased3-Methylcrotonyl-CoA carboxylase deficiency (van Hove et al., 1995); 3-hydroxy-3-methylglutaryl-CoA lyase deficiency (Bischof et al., 2004; Santarelli et al., 2013; Dos Santos Mello et al., 2015; Václavík et al., 2020); 3-methylglutaconic aciduria type 1 (Tavasoli et al., 2017); Leigh syndrome (Balasubramaniam et al., 2017); holocarboxylase synthetase deficiency (Yokoi et al., 2009)
    DecreasedTraumatic brain injury (Jeter et al., 2013)
    UrineIncreased3-Methylcrotonyl-CoA carboxylase deficiency (van Hove et al., 1995); multiple carboxylase deficiency (Nakanishi and Shimizu, 1993; Maeda et al., 2008); biotin deficiency (Stratton et al., 2011)
    2-Methyl-3-hydroxy-butyrylcarnitine (C5-OH-M)BloodIncreasedMitochondrial acetoacetyl-CoA thiolase deficiency (Catanzano et al., 2010); mitochondrial 2-methylacetoacetyl-CoA thiolase deficiency (Ngu et al., 2008)
    3-Methylglutaconylcarnitine (C5:1-M-DC)BloodIncreased3-Hydroxy-3-methylglutaryl-CoA lyase deficiency (Václavík et al., 2020)
    UrineIncreased3-Methylglutaconic aciduria (Jooste et al., 1994)
    3-Hydroxy‐3‐methylglutaryl-carnitine (C5:1-M-OH-DC)BloodIncreased3-Hydroxy-3-methylglutaryl-CoA lyase deficiency (Václavík et al., 2020)
    3-Hydroxy-hexanoylcarnitine (C6-OH)UrineIncreasedMetabolic syndrome (Esperanza et al., 2020)
    Adipylcarnitine (C6-DC)BloodIncreasedPulmonary arterial hypertension (Mey et al., 2020)
    UrineIncreasedGlutaric aciduria type 1 (Matsumoto et al., 1990); 3-hydroxy-3-methylglutaryl-CoA lyase deficiency (Grunert et al., 2017)
    Dehydroadipylcarnitine (C6:1-DC)UrineDecreasedGlutaric aciduria type 1 (Matsumoto et al., 1990)
    Pimelylcarnitine (C7-DC)BloodIncreasedDiastolic heart failure (Zordoky et al., 2015)
    DecreasedPsoriasis (Ottas et al., 2017)
    Suberylcarnitine (C8-DC)BloodIncreasedPulmonary arterial hypertension (Mey et al., 2020); type 2 diabetes (Adams et al., 2009)
    Dodecanedioylcarnitine (C12-DC)BloodIncreasedChronic fatigue syndrome (Reuter and Evans, 2011)
    UrineIncreasedCarnitine palmitoyltransferase 2 deficiency (Fontaine et al., 1998)
    3-Hydroxy-tetradecanoylcarnitine (C14-OH)BloodIncreasedCardiovascular diseases in type 2 diabetes (Zhao et al., 2020)
    Tetracanedioylcarnitine (C14-DC)UrineIncreasedZellweger syndrome (Duranti et al., 2008); infantile Refsum disease (Duranti et al., 2008); D-bifunctional protein deficiency (Duranti et al., 2008)
    3-Hydroxy-tetradecenoylcarnitine (C14:1-OH)BloodDecreasedPsoriasis (Chen et al., 2021); coronary artery disease (Shah et al., 2010)
    UrineIncreasedObstructive sleep apnea (Cho et al., 2017b); mitochondrial trifunctional protein deficiency (Park et al., 2009)
    3-Hydroxy-hexadecanoylcarnitine (C16-OH)BloodIncreasedType 2 diabetes (Mai et al., 2013; Zhang et al., 2014; Hameed et al., 2020); long-chain 3-hydroxy acyl-CoA dehydrogenase deficiency (Karall et al., 2015); mitochondrial trifunctional protein deficiency (Park et al., 2009)
    DecreasedPsoriasis (Chen et al., 2021)
    3-Hydroxy-hexadecenoylcarnitine (C16:1-OH)BloodIncreasedDiastolic heart failure (Hunter et al., 2016); systolic heart failure (Hunter et al., 2016)
    DecreasedIntracerebral hemorrhage (Zhang et al., 2017b); psoriasis (Chen et al., 2021); coronary artery disease (Shah et al., 2010)
    Hexadecanedioylcarnitine (C16-DC)BloodIncreasedPeroxisomal biogenesis disorders (Rizzo et al., 2003)
    UrineIncreasedZellweger syndrome (Duranti et al., 2008); infantile Refsum disease (Duranti et al., 2008); D-bifunctional protein deficiency (Duranti et al., 2008)
    3-Hydroxysteroylcarnitine (C18‐OH)BloodIncreasedCoronary artery disease (Shah et al., 2010)
    3-Hydroxyoleylcarnitine (C18:1‐OH)BloodIncreasedChronic fatigue syndrome (Reuter and Evans, 2011); mitochondrial trifunctional protein deficiency (Park et al., 2009); psoriasis (Chen et al., 2021)
    Octadecanedioylcarnitine (C18-DC)BloodIncreasedPeroxisomal biogenesis disorders (Rizzo et al., 2003)
    UrineIncreasedZellweger syndrome (Duranti et al., 2008); infantile Refsum disease (Duranti et al., 2008); D-bifunctional protein deficiency (Duranti et al., 2008)
  • TABLE 8

    Proteins directly involved in acylcarnitine biosynthesis and transport or directly affected by acylcarnitines

    Protein and Identifier
    (UniProt ID for Human Protein)    		InvolvementLocalizationReference
    Carnitine acetyltransferase (CrAT)
    EC 2.3.1.7 (UniProtKB: P43155)    		Catalyzes the reversible transfer of acyl groups (up to C4) from carnitine to CoA and regulates the acyl-CoA/CoA ratio and availability of free CoA during intensified fatty acid metabolism.Mitochondrial matrix, peroxisomal matrix, endoplasmic reticulum, nucleus, and cardiomyocyte cytosolWu et al., 2003; Hsiao et al., 2004; Stephens et al., 2007
    Carnitine octanoyltransferase (CrOT)
    EC 2.3.1.137 (UniProtKB: Q9UKG9)    		Catalyzes reversible transfer of acyl groups (C6–12, can go up to C16) from CoA to carnitine. Metabolism of branched chain fatty acids.Peroxisomal matrixFerdinandusse et al., 1999; Jogl et al., 2005
    Carnitine palmitoyltransferase 1 (CPT1)
    EC 2.3.1.21    		Catalyzes reversible transfer of the acyl group of long-chain fatty acid-CoA conjugates onto carnitine. Broad specificity to acyl group, over the range of C8–C18, optimal substrate palmitoyl-CoA. Forward reaction inhibited by palmitoylcarnitine and malonyl-CoA.Outer mitochondrial membraneMcGarry and Brown, 1997
    CPT1A – liver isoform
    UniProtKB: P50416    		Expressed in most tissues. Low Km value for carnitine, sensitive to malony-CoA.Outer mitochondrial membrane
    CPT1B – muscle isoform
    UniProtKB: Q92523    		Highest expression in heart and skeletal muscle, no expression in liver and kidney. High Km value for carnitine, sensitive to malony-CoA.Outer mitochondrial membrane
    CPT1C – brain isoform
    UniProtKB: Q8TCG5    		Highest expression in brain and testis. Catalytic activity negligible but can bind malonyl-CoA. Regulates energy homeostasis and involved in ceramide biosynthesis and regulation.Conflicting reports on localization in mitochondria or endoplasmic reticulumPrice et al., 2002; Wolfgang et al., 2006; Sierra et al., 2008
    Carnitine palmitoyltransferase 2 (CPT2)
    EC 2.3.1.21 (UniProtKB: P23786)    		Catalyzes the transfer of the acyl group of long-chain fatty acid- carnitine conjugates onto CoA. Loss of CPT2 disables the acylcarnitine-mediated mitochondrial oxidation of long-chain fatty acids.Inner mitochondrial membranePereyra et al., 2017
    Carnitine/acylcarnitine translocase (CACT) (UniProtKB: O43772)Transport of acylcarnitines and carnitine across the mitochondrial inner membrane to and from mitochondrial matrix. Support of mitochondrial fatty acid-oxidation pathway.Inner mitochondrial membraneConsole et al., 2014
    Organic cation transporter 1 (OCT1) SLC22A1 (UniProtKB: O15245)Involved in hepatic acylcarnitine efflux. Associated with serum acylcarnitine levels.Cell membraneKim et al., 2017
    Organic cation novel type 2 transporter (OCTN2) SLC22A5 (UniProtKB: O76082)Involved in transport of acetylcarnitine.Cell membraneKido et al., 2001; Kobayashi et al., 2007
  • TABLE 9

    Effects of acetylcarnitine supplementation

    Disease/ConditionPositive Outcome of SupplementationNegative/Neutral Effect
    Peripheral nervous system diseasesDe Grandis et al., 1995; Onofrj et al., 1995; Scarpini et al., 1997; Grandis, 1998; Hart et al., 2004; Bianchi et al., 2005; Ghirardi et al., 2005a,b; Herzmann et al., 2005; Maestri et al., 2005; Flatters et al., 2006; Osio et al., 2006; Youle and Osio, 2007; Memeo and Loiero, 2008; Xiao and Bennett, 2008; Traina et al., 2009; Valcour et al., 2009; Campone et al., 2013; Li et al., 2016; Sun et al., 2016a; Cruccu et al., 2017Hershman et al., 2013; 2018; Callander et al., 2014; Curran et al., 2019
    Alzheimer’s diseaseBonavita, 1986; Battistin et al., 1989; Bella et al., 1990; Passeri et al., 1990; Rai et al., 1990; Spagnoli et al., 1991; Parnetti et al., 1993; Pettegrew et al., 1995; Thal et al., 1996; Brooks et al., 1998; Bianchetti et al., 2003; Chan et al., 2008; 2010; Remington et al., 2009; 2015a,b; 2016; Gavrilova et al., 2011; Bersani et al., 2013; Jeong et al., 2017Campi et al., 1990; Thal et al., 2000
    Cognitive dysfunctionHerrmann et al., 1990; Lino et al., 1992; Chan et al., 2010; Amen et al., 2011; Remington et al., 2015a,b
    DementiaPasseri et al., 1988; Battistin et al., 1989; Gambi et al., 1989; Goety et al., 1990; Sinforiani et al., 1990; Salvioli and Neri, 1994; Remington et al., 2016; Yang et al., 2018Pueschel, 2006
    Multiple sclerosisFamularo et al., 1999; Tomassini et al., 2004; Maestri et al., 2005
    Neurodegenerative diseasesCalabrese et al., 2003
    PainOnofrj et al., 1995; Scarpini et al., 1997; Biagiotti and Cavallini, 2001; De Grandis and Minardi, 2002; Herzmann et al., 2005; Sima et al., 2005; Osio et al., 2006; Rossini et al., 2007; Youle and Osio, 2007; Memeo and Loiero, 2008; Xiao and Bennett, 2008; Janiri et al., 2009; Valcour et al., 2009; Malaguarnera et al., 2011b; Leombruni et al., 2015; Park et al., 2016; Cruccu et al., 2017
    Depressive disorderTempesta et al., 1987; Guarnaschelli et al., 1988; Bella et al., 1990; Cipolli and Chiari, 1990; Garzya et al., 1990; Salvioli and Neri, 1994; Pettegrew et al., 2002; Cavallini et al., 2004; Zanardi and Smeraldi, 2006; Rossini et al., 2007; Malaguarnera et al., 2011a; Bersani et al., 2013; Leombruni et al., 2015; Suzuki et al., 2019Tomassini et al., 2004; Brennan et al., 2013
    Fatigue, dystrophyVermeulen and Scholte, 2004; Rossini et al., 2007; Malaguarnera et al., 2008; 2011b,c; 2014; Benedini et al., 2009; Hoffman et al., 2010; Sun et al., 2016a; Pereira et al., 2018Ledinek et al., 2013; Martí-Carvajal et al., 2019
    IschemiaPostiglione et al., 1990; Gasparetto et al., 1991; Postiglione et al., 1991; Corbucci et al., 1992; Adembri et al., 1994
    Nerve degenerationHart et al., 2002
    Diabetic neuropathiesDe Grandis and Minardi, 2002; Sima et al., 2005
    NeuralgiaMemeo and Loiero, 2008; Valcour et al., 2009; Xiao et al., 2012; Callander et al., 2014; Curran et al., 2016; Cruccu et al., 2017Hershman et al., 2013; 2018
    HyperammonemiaSiciliano et al., 2006; Malaguarnera et al., 2011c; Suzuki et al., 2017
    Type 2 diabetesGiancaterini et al., 2000; Turpeinen et al., 2000; Ruggenenti et al., 2009; Fernandez et al., 2013; Li et al., 2016Parvanova et al., 2018; Condorelli et al., 2019; Rolim et al., 2019
  • TABLE 10

    Effects of propionylcarnitine supplementation

    Disease/ConditionPositive Outcome of SupplementationNegative/Neutral Effect
    Depressive disorderCavallini et al., 2004
    Erectile dysfunctionGentile et al., 2004; 2009; Cavallini et al., 2005; Morano et al., 2007; Gianfrilli et al., 2012
    Penile indurationCavallini et al., 2002Safarinejad et al., 2007
    Ulcerative colitisGasbarrini et al., 2003; Mikhailova et al., 2011; Scioli et al., 2014
    Peripheral arterial diseaseScanlon, 1985; Bolognesi et al., 1995; Taylor et al., 1996; Capecchi et al., 1997; Cittanti et al., 1997; Di Marzo et al., 1999; Loffredo et al., 2006; 2013; Santo et al., 2006; Signorelli et al., 2006a,b; De Marchi et al., 2012
    Intermittent claudicationBrevetti et al., 1995; 1997; 1999; Taylor et al., 1996; Dal Lago et al., 1999; Di Marzo et al., 1999; De Barker et al., 2001; Hiatt et al., 2001; Strano, 2002; Marchi et al., 2012; Luo et al., 2013Hiatt et al., 2011
    IschemiaChiddo et al., 1991; Greco et al., 1992; Lagioia et al., 1992
    Heart failureMancini et al., 1992; Anand et al., 1998The Investigators of the Study, 1999 (no effect on exercise duration)
    Diabetes mellitusGreco et al., 1992 (diabetic angiopathy)
    Peripheral vascular diseasesGreco et al., 1992; Pola et al., 1992; Allegra et al., 2008; Riccioni et al., 2008
    Reperfusion injuryLango et al., 2005
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Acylcarnitines

Maija Dambrova, Marina Makrecka-Kuka, Janis Kuka, Reinis Vilskersts, Didi Nordberg, Misty M. Attwood, Stefan Smesny, Zumrut Duygu Sen, An Chi Guo, Eponine Oler, Siyang Tian, Jiamin Zheng, David S. Wishart, Edgars Liepinsh and Helgi B. Schiöth
Pharmacological Reviews July 1, 2022, 74 (3) 506-551; DOI: https://doi.org/10.1124/pharmrev.121.000408
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