Measures protective of mitochondrial and peroxisomal Beta-Oxidation in High Fat Ketogenic Diets

Avoid:

Mitochondrial beta-oxidation inhibitors

Endogenous compounds, including cytokines and female sex hormones

Toxins, including ethanol, toximul, phthalates

Potentially mitochondrion-toxic drugs

 

Remarks:

Inhibition affects the respiratory chain and the mitochondrial genome, and increases production of ROS, which fosters lipid peroxidation (1,2). Salicylic acid and valproic acid may facilitate permeability transition pores by calcium in hepatocytes.( Pessayre D. et al., Hepatotoxicity due to Mitochondrial Dysfunction. Cell Biol Toxicol, 1999; 15 (6): 367-73; Lemasters  et al. The Mitochondrial Permeability Transition in Cell Death: a Common Mechanism in Necrosis, Apoptosis and Autophagy. Biochem. Biophys. Acta.1998 (1366), 177-196).

 

Inhibitors of mitochondrial beta-oxidation enzymes:

Tetracyclines, several 2-arylpropionate anti-inflammatory drugs, amineptine, and tianeptine are inhibitors of beta-oxidation enzymes.

 

Inhibitors of beta-oxidation and oxidative phosphorylation:

Endogenous bile acids, amiodarone, perhexiline, and diethylaminoethooxyhexestrol are inhibitors of beta-oxidation and oxidative phosphorylation. When beta-oxidation is severely impaired, fatty acids which are poorly oxidized by mitochondria are mainly esterified into triglycerides. High triglycerides in patients undergoing HFKD treatments may be a sign of impaired beta-oxidation. (Fromenty B., Pessayre D. Impaired Mitochondrial Function in Microvesicular Steatosis. Effects of Drugs, Ethanol, Hormones and Cytokines. J. Hepatol. 1997; 26 Suppl 2: 43-53).

Propofol

Propofol is used as an anesthetic and occasionally for the treatment of refractory status epilepticus, and can cause a rare but frequently fatal complication, the propofol infusion syndrome. Propofol infusion syndrome is caused by impaired fatty acid oxidation. Substances like propofol which impair fatty acid oxidation may pose an increased risk if combined with ketogenic diet. (Baumeister FA et al. Fatal Propofol Infusion Syndrome in association with Ketogenic Diet. Neuropediatrics.2004 Aug; 35(4):250-2).

Felbamate

Reduction in valproic acid (valproate sodium) clearance by felbamate is caused by the inhibition of beta-oxidation. (Riva R. et al. Pharmacokinetic Interactions between Antiepileptic drugs. Clinical Considerations, Clin. Pharmacokinet. 1996 Dec; 31 (6):470-93 and Glue P. et al. Pharmacokinetic Interactions with felbamate. In Vitro-in Vivo Correlation. Clin Pharmacokinet. 1997 Sep; 33 (3): 214-24).

Pivalate-conjugated Antibiotics

Pivalate-conjugared antibiotics cause excretion of pivaloyl-carnitine, which can lead to carnitine depletion; tissues can become low enough to limit fatty acid oxidation.(Stanley CA. Carnitine Deficiency Disorders in Children. Ann NY Acad Sci. 2004 Nov; 1033:42-51).

Pivalic Acid and Valproic Acid

Prodrugs with pivalic acid and valproic acid decrease L.carnitine concentration in plasma and tissues by urinary excretion  of acylcarnitine as pivaloylcarnitine and valproylcarnitine respectively. (Okamura N. et al. Involvement of Recognition and Interaction of Carnitine Transporter in the Decrease of L.Carnitine Concentration Induced by Pivalic Acid and Valproic Acid. Pharm Res . 2006 Jul 7).

Pirprofen

Pirprofen inhibits the mitochondrial beta-oxidation of fatty acids in mice, thus explaining the microvesicular steatosis observed in mice and in some human subjects. (Geneve J et al. Inhibition of Mitochondrial beta-oxidation of fatty Acids by Pirprofen. Role in Microvesicular Steatosis due to this Nonsteroidal Anti-inflammatory Drug.  Amer Soc for Pharma and Exp Thera, Sep 1987, vol 242, issue 3, 1133-1137).

Phenylalanine

In view of the importance of succinate dehydrogenase and respiratory chain complexes for the maintenance of energy supply to brain, energy deficit may contribute to the phenylalanine neurotoxicity in PKU. (Rech VC et al. Inhibition of the Mitochondrial Respiratory Chain by Phenylalanine in Rat Cerebral Cortex.Neurochem Res. 2002 May;27(5):353-7).

Toximul

Toximul is an industrial surfactant used in pesticides, fungicides and bactericides; in pulp production; as an emulsifier for paraffin oil; and as a treatment for pineapple plants to inhibit opening of pineapple flowers. Oxidation of (1-14C) palmitate has been shown to be inhibited by the industrial surfactant Toximul. (Murphy MG et al. Beta-oxidation of (1-14 C) Palmitic Acid by Mouse Astrocytes in Primary Culture: Effects of Agents Implicated in the Encephalopathy of Reye’s Syndrome. J Neurosci Res. 1992 Nov; 33(3):445-54).

Salicylates

There is selective inhibition of mitochondrial oxidation of medium-chain (octanoic acid) and long chain (palmitic acid) fatty acids by salicylic acid. (Yoshida Y. et al. Effect of Salicylic Acid on Mitochondrial-Peroxisomal Fatty Acid Catabolism. Pediatr Res 1988 Mar;23(3):338-41).

Hyper Ammonemia

Viral Infections: (Mitochondria and Viruses (unreviewed) asanjeev.anand@usask.ca, 2007).

Nasally-administered Flu B has profound effects on hepatic fatty-acid metabolism, particularly beta-oxidation. (Murphy MG et al. Abnormalities in Hepatic Fatty-Acid Metabolism in a Surfactant/Influenza B Virus Mouse Model for Acute Encephalopathy. Biochem Biophys Acta. 1996 Apr 12; 1315(3):208-16).

Synergisms

Toximul in Conjunction with Viral Infection

(see above)

 

Enhancement of mitochondrial beta-oxidation:

Carnitine

(refs. to be added)

Eicosapentaenoic acid (Willumsen N. et al. Eicosapentaenoic  Acid, but not Docosahexaenoic Acid, Increases Mitochondrial Fatty Acid Oxidation and Upregulates 2,4-dienoyl-CoA Reductase Gene Expression in Rats. Lipids. 1996 Jun;31 (6): 579-92).

Higher calcium and vitamin D have been shown to acutely stimulate postprandial thermogenesis and fat oxidation (Soares  MJ et al. Dairy Calcium and Vitamin D Stimulate Postprandial Thermogenesis: Effect of Sequential Meals. Asia Pac J Clin Nutr. 2004; 13 (Suppl): S56).

 

Enhancement of peroxisomal beta-oxidation:

High fat diets have been shown to induce peroxisomal beta-oxidation activity only if they also contain C20 and C22 fatty acids. DHA and EPA esters were shown to be much less effective than fish oil in increasing fatty acid oxidation. (Veerkamp JH, Zevenbergen JL.  Effect of Dietary Fat on Total and Peroxisomal Fatty Acid Oxidation in Rat Tissues.  Biochim. Biophys. Acta. 1986 Aug 14; 878 (1): 102-9

Dietary Sesamin and Docosahexaenoic and Eicosapentaenoic Acids Synergistically Increase the Gene Expression of Enzymes Involved in Hepatic Peroxisomal Fatty Acid Oxidation in Rats.(Metabolism, 2006 Mar; 55 (3): 381-90).

 

Enhancement of peroxisome proliferator-activated receptor alpha (PPAR alpha):

The genes encoding the classical beta-oxidation pathway in liver are transcriptionally regulated by PPAR alpha. HFKD upregulates PPAR alpha (Cullingford T.).

 

 Signs of faulty beta-oxidation:

Elevated triglycerides (see above)

Hunger

Fatty acid oxidation ….especially in the liver, appears to be signaled to the brain by vagal afferents that affect eating. (Scharrer E. Control of Food Intake by Fatty Acid Oxidation and Ketogenesis. Nutrition.1999 Sep; 15 (9): 704-14)

Low body core temperature