Carnitine metabolism (Homo sapiens)
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The mitochondrial carnitine system catalyzes the transport of long-chain fatty acids into the mitochondrial matrix where they undergo beta oxidation. This transport system consists of the malonyl-CoA sensitive carnitine palmitoyltransferase I (CPT-I) localized in the mitochondrial outer membrane, the carnitine:acylcarnitine translocase, an integral inner membrane protein, and carnitine palmitoyltransferase II localized on the matrix side of the inner membrane. (Kerner and Hoppel, 2000).
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While humans are capable of synthesizing carnitine de novo, the enzyme that catalyzes the last reaction of the biosynthetic pathway is found only in liver and kidney cells, and at very low levels in brain cells. Other tissues that require carnitine, such as muscle, are dependent on transport systems that mediate its export from the liver and uptake by other tissues (Kerner & Hoppel 1998). The specific transport systems responsible for liver export have been characterized biochemically in model organisms but specific transport proteins have not yet been identified. OCTN2 is the major transporter responsible for carnitine uptake in extrahepatic tissues, as demonstrated both by the biochemical characterization of overexpressed recombinant human protein (Tamai et al. 1998) and by the appearance of symptoms of carnitine deficiency in humans lacking a functional SLC22A5 gene (Seth et al. 1999; reviewed by Longo et al. 2016).
In the nucleus, cellular retinoic acid-binding protein 1 or 2 (CRABP1 or 2), bound to all-trans-retinoic acid (atRA), directly binds to the heterodimeric complex of retinoic acid receptor alpha RXRA) and peroxisome proliferator-activated receptor delta (PPARD). When bound to PPARD, atRA can significantly increase the expression of proteins involved in fatty acid oxidation such as CPT1A via its induction of PPARD (Amengual et al. 2012).
Mid1-interacting protein 1 (MID1IP1, aka MIG12, SPOT14R, S14R) plays a role in the regulation of lipogenesis in the liver. It is rapidly upregulated by processes that induce lipogenesis (enhanced glucose metabolism, thyroid hormone administration) (Tsatsos et al. 2008). MID1IP1 forms a heterodimer with thyroid hormone-inducible hepatic protein (THRSP, aka SPOT14, S14), proposed to play the same role in lipogenesis as MID1IP1 (Aipoalani et al. 2010). This complex can polymerise acetyl-CoA carboxylases 1 and 2 (ACACA and B), the first committed enzymes in fatty acid (FA) synthesis. Polymerisation enhances ACACA and ACACB enzyme activities (Kim et al. 2010).
Mid1-interacting protein 1 (MID1IP1, aka MIG12, SPOT14R, S14R) plays a role in the regulation of lipogenesis in the liver. It is rapidly upregulated by processes that induce lipogenesis (enhanced glucose metabolism, thyroid hormone administration) (Tsatsos et al. 2008). MID1IP1 forms a heterodimer with thyroid hormone-inducible hepatic protein (THRSP, aka SPOT14, S14), proposed to play the same role in lipogenesis as MID1IP1 (Aipoalani et al. 2010). This complex can polymerise acetyl-CoA carboxylases 1 and 2 (ACACA and B), the first committed enzymes in fatty acid (FA) synthesis. Polymerisation enhances ACACA and ACACB enzyme activities (Kim et al. 2010).