Inhibition of hepatic carnitine palmitoyl-transferase I (CPT IA) by valproyl-CoA as a possible mechanism of valproate-induced steatosis

Aires, C. C. P.; IJlst, Lodewijk; Stet, Femke S.; Prip‐Buus, Carina; Almeida, Isabel Tavares de; Durán, Marinus; Wanders, Ronald J. A.; Silva, Margarida F. B.

doi:10.1016/j.bcp.2009.10.011

Cited by 82 publications

(68 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…39 In further support of a contribution of impaired mitochondrial b-oxidation to steatosis, inhibition of CPT-1 has been identified as a possible underlying mechanism in drug-induced steatosis. 40 Development of steatosis was also favored by other defects of mitochondrial b-oxidation such as heterozygous deletion of mitochondrial trifunctional protein or knockdown of long chain acyl-CoA dehydrogenase. 41,42 Similarly, impairment of VLDL synthesis has been implicated as a possible contributor to fat accumulation in hepatocytes in a polygenic mouse model of NASH.…”

Section: Discussionmentioning

confidence: 99%

Stimulation of fat accumulation in hepatocytes by PGE2-dependent repression of hepatic lipolysis, β-oxidation and VLDL-synthesis

Henkel

Frede

Schanze

et al. 2012

Laboratory Investigation

View full text Add to dashboard Cite

Hepatic steatosis is recognized as hepatic presentation of the metabolic syndrome. Hyperinsulinaemia, which shifts fatty acid oxidation to de novo lipogenesis and lipid storage in the liver, appears to be a principal elicitor particularly in the early stages of disease development. The impact of PGE 2 , which has previously been shown to attenuate insulin signaling and hence might reduce insulin-dependent lipid accumulation, on insulin-induced steatosis of hepatocytes was studied. The PGE 2 -generating capacity was enhanced in various obese mouse models by the induction of cyclooxygenase 2 and microsomal prostaglandin E-synthases (mPGES1, mPGES2). PGE 2 attenuated the insulin-dependent induction of SREBP-1c and its target genes glucokinase and fatty acid synthase. Nevertheless, PGE 2 enhanced incorporation of glucose into hepatic triglycerides synergistically with insulin. This was most likely due to a combination of a PGE 2 -dependent repression of (1) the key lipolytic enzyme adipose triglyceride lipase, (2) carnitine-palmitoyltransferase 1, a key regulator of mitochondrial b-oxidation, and (3) microsomal transfer protein, as well as (4) apolipoprotein B, key components of the VLDL synthesis. Repression of PGC1a, a common upstream regulator of these genes, was identified as a possible cause. In support of this hypothesis, overexpression of PGC1a completely blunted the PGE 2 -dependent fat accumulation. PGE 2 enhanced lipid accumulation synergistically with insulin, despite attenuating insulin signaling and might thus contribute to the development of hepatic steatosis. Induction of enzymes involved in PGE 2 synthesis in in vivo models of obesity imply a potential role of prostanoids in the development of NAFLD and NASH.

show abstract

Section: Discussionmentioning

confidence: 99%

Stimulation of fat accumulation in hepatocytes by PGE2-dependent repression of hepatic lipolysis, β-oxidation and VLDL-synthesis

Henkel

Frede

Schanze

et al. 2012

Laboratory Investigation

View full text Add to dashboard Cite

show abstract

“…Indeed, this enzyme can be inhibited by VPA (Fig. 3), amiodarone, and tamoxifen [102,107,132]. Interestingly, troglitazone is able to inhibit long-chain acyl-CoA synthase (ACS) (Fig.…”

Section: Drug-induced Severe Inhibition Of Mitochondrial B-oxidation mentioning

confidence: 97%

Drug-induced toxicity on mitochondria and lipid metabolism: Mechanistic diversity and deleterious consequences for the liver

Begriche¹,

Massart²,

Robin³

et al. 2011

Journal of Hepatology

473

413

View full text Add to dashboard Cite

Numerous investigations have shown that mitochondrial dysfunction is a major mechanism of drug-induced liver injury, which involves the parent drug or a reactive metabolite generated through cytochromes P450. Depending of their nature and their severity, the mitochondrial alterations are able to induce mild to fulminant hepatic cytolysis and steatosis (lipid accumulation), which can have different clinical and pathological features. Microvesicular steatosis, a potentially severe liver lesion usually associated with liver failure and profound hypoglycemia, is due to a major inhibition of mitochondrial fatty acid oxidation (FAO). Macrovacuolar steatosis, a relatively benign liver lesion in the short term, can be induced not only by a moderate reduction of mitochondrial FAO but also by an increased hepatic de novo lipid synthesis and a decreased secretion of VLDL-associated triglycerides. Moreover, recent investigations suggest that some drugs could favor lipid deposition in the liver through primary alterations of white adipose tissue (WAT) homeostasis. If the treatment is not interrupted, steatosis can evolve toward steatohepatitis, which is characterized not only by lipid accumulation but also by necroinflammation and fibrosis. Although the mechanisms involved in this aggravation are not fully characterized, it appears that overproduction of reactive oxygen species by the damaged mitochondria could play a salient role. Numerous factors could favor drug-induced mitochondrial and metabolic toxicity, such as the structure of the parent molecule, genetic predispositions (in particular those involving mitochondrial enzymes), alcohol intoxication, hepatitis virus C infection, and obesity. In obese and diabetic patients, some drugs may induce acute liver injury more frequently while others may worsen the pre-existent steatosis (or steatohepatitis).

show abstract

“…Perhaps, because of side effects this type of pharmacological approach on diabetes control could result blocking selectively liver CPT1 isoform; in fact, this isoform is also implicated in CNS control of food intake [15]. In addition, some negative aspects were already highlighted in previous studies such as steatosis [16] and apoptosis [17,18]; the latter aspect as to generate a new stream of research to anticancerogenic action due to CPT1 inhibition [19,20]. Moreover, other dangerous negative aspects of CPT blocking such as cardiac mitochondrial toxicity [21], cardiac hypertrophy [22,23] and mortality for prolonged inhibition [24] emerged in other studies; consider that diabetes is a chronic disease and as such should be treated, the continued blockade of the CPT may be contraindicated?…”

Section: Current Research In Diabetes and Obesity Journalmentioning

confidence: 99%

"Diabetes Mellitus: could the Inhibition of a Single Enzyme (CPT-1) Involved in the Beta-Oxidation Process Improve this Complex Disease?"

Chiodi¹

2017

CRDOJ

View full text Add to dashboard Cite

Inhibition of hepatic carnitine palmitoyl-transferase I (CPT IA) by valproyl-CoA as a possible mechanism of valproate-induced steatosis

Cited by 82 publications

References 38 publications

Stimulation of fat accumulation in hepatocytes by PGE2-dependent repression of hepatic lipolysis, β-oxidation and VLDL-synthesis

Stimulation of fat accumulation in hepatocytes by PGE2-dependent repression of hepatic lipolysis, β-oxidation and VLDL-synthesis

Drug-induced toxicity on mitochondria and lipid metabolism: Mechanistic diversity and deleterious consequences for the liver

"Diabetes Mellitus: could the Inhibition of a Single Enzyme (CPT-1) Involved in the Beta-Oxidation Process Improve this Complex Disease?"

Contact Info

Product

Resources

About