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Role of 3-Hydroxy Fatty Acid-Induced Hepatic Lipotoxicity in Acute Fatty Liver of Pregnancy

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Role of 3-Hydroxy Fatty Acid-Induced Hepatic Lipotoxicity in Acute Fatty Liver of Pregnancy International Journal of Molecular Sciences Review Role of 3-Hydroxy Fatty Acid-Induced Hepatic Lipotoxicity in Acute Fatty Liver of Pregnancy Sathish Kumar Natarajan 1 ID and Jamal A. Ibdah 2,3,4,* 1 Department of Nutrition and Health Sciences, University of Nebraska-Lincoln, Lincoln, NE 68583-0806, USA; [email protected] 2 Division of Gastroenterology and Hepatology, University of Missouri, Columbia, MO 65212, USA 3 Department of Medical Pharmacology and Physiology, University of Missouri, Columbia, MO 65212, USA 4 Harry S. Truman Memorial Veterans Medical Center, Columbia, MO 65201, USA * Correspondence: [email protected]; Tel.: +1-573-882-7349; Fax: +1-573-884-4595 Received: 1 January 2018; Accepted: 16 January 2018; Published: 22 January 2018 Abstract: Acute fatty liver of pregnancy (AFLP), a catastrophic illness for both the mother and the unborn offspring, develops in the last trimester of pregnancy with significant maternal and perinatal mortality. AFLP is also recognized as an obstetric and medical emergency. Maternal AFLP is highly associated with a fetal homozygous mutation (1528G>C) in the gene that encodes for mitochondrial long-chain hydroxy acyl-CoA dehydrogenase (LCHAD). The mutation in LCHAD results in the accumulation of 3-hydroxy fatty acids, such as 3-hydroxy myristic acid, 3-hydroxy palmitic acid and 3-hydroxy dicarboxylic acid in the placenta, which are then shunted to the maternal circulation leading to the development of acute liver injury observed in patients with AFLP. In this review, we will discuss the mechanistic role of increased 3-hydroxy fatty acid in causing lipotoxicity to the liver and in inducing oxidative stress, mitochondrial dysfunction and hepatocyte lipoapoptosis. Further, we also review the role of 3-hydroxy fatty acids in causing placental damage, pancreatic islet β-cell glucolipotoxicity, brain damage, and retinal epithelial cells lipoapoptosis in patients with LCHAD deficiency. Keywords: acute fatty liver of pregnancy; 3-hydroxy fatty acids; lipoapoptosis; fatty acid oxidation 1. Fatty Acid Oxidation Humans have three major types of fatty acid oxidation pathways that feeds high energy reducing equivalents to the mitochondria for the generation of ATP. Mitochondrial β-oxidation, peroxisome β-oxidation, and microsomal !-oxidation pathways are the three types of oxidation for long chain fatty acids. 1.1. Mitochondrial Fatty Acid Oxidation Mitochondrial long chain fatty acid β-oxidation is the predominant cellular oxidation pathway with the production of acetyl-Coenzyme A (CoA), which feeds into the tricarboxylic acid (TCA) cycle for the high-energy ATP production via the mitochondrial electron transport chain. Fatty acids are acylated and activated by fatty acyl-CoA synthetase in the outer mitochondrial membrane. Carnitine acyl transferase I converts acyl-CoA into fatty acyl carnitine, which is translocated across the inner mitochondrial membrane by carnitine translocase. Carnitine acyl transferase II in the inner mitochondrial membrane catalyzes the formation of fatty acyl-CoA for the initiation of the β-oxidation pathway [1–4]. Classic mitochondrial fatty acid β-oxidation involves a four-step process: dehydrogenation, hydration, dehydrogenation and thiolytic cleavage (Figure1). Acyl-CoA dehydrogenase initiates β-oxidation by catalyzing the first dehydrogenation step, forms a double Int. J. Mol. Sci. 2018, 19, 322; doi:10.3390/ijms19010322 www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2018, 19, 322 2 of 17 Int. J. Mol. Sci. 2018, 19, x 2 of 16 bond, and converts fatty acyl-CoA into trans-enoyl-CoA. The next three steps in the β-oxidation of longbond, chainand converts fatty acids fatty acyl-CoA are catalyzed into trans-enoyl-CoA. by mitochondrial The tri-functionalnext three steps protein in the β (MTP).-oxidation MTP of is a complexlong chain heterooctamer fatty acids are protein catalyzed attached by mitochondrial to the inner tri-functional mitochondrial protein membrane (MTP). MTP with is a 4 complexα-subunits andheterooctamer 4β-subunits encodedprotein attached by the HADHAto the innerand mitochondrialHADHB gene, membrane respectively. with The4α-subunitsα-subunit and contains 4β- longsubunits chain enoyl-CoAencoded by the hydratase HADHA activity and HADHB in its gene, amino-terminal respectively. domain,The α-subunit while contains long chain long chain hydroxy acyl-CoAenoyl-CoA dehydrogenase hydratase activity (LCHAD) in its activity amino-terminal resides at domain, the carboxyl-terminal while long chain domain. hydroxy The acyl-CoAβ-subunit containsdehydrogenase the long chain (LCHAD) 2-ketoacyl-CoA activity resides thiolase at the activity, carboxyl-terminal which catalyzes domain. the fourthThe β-subunit step in βcontains-oxidation cycle.the Enoyl-CoAlong chain 2-ketoacyl-CoA hydratase in thethiolaseα-subunit activity, catalyzes which catalyzes the conversion the fourth of step enoyl-CoA in β-oxidation to 3-hydroxy cycle. acyl-CoA.Enoyl-CoA Next, hydratase 3-hydroxy in the acyl-CoA α-subunit is catalyzes oxidized the to conversion form 3-keto of enoyl-CoA acyl-CoA to by 3-hydroxy the enzyme acyl-CoA. LCHAD. Next, 3-hydroxy acyl-CoA is oxidized to form 3-keto acyl-CoA by the enzyme LCHAD. The final step The final step of β-oxidation is catalyzed by thiolase, which generates acetyl-CoA and a fatty acyl-CoA. of β-oxidation is catalyzed by thiolase, which generates acetyl-CoA and a fatty acyl-CoA. The cycle The cycle of β-oxidation proceeds with a shorter fatty acyl-CoA for the continuous energy demand of β-oxidation proceeds with a shorter fatty acyl-CoA for the continuous energy demand and supply and supply of acetyl-CoA. Pediatric defects in mitochondrial fatty acid oxidation (FAO) are recessively of acetyl-CoA. Pediatric defects in mitochondrial fatty acid oxidation (FAO) are recessively inherited inheritedand have and emerged have emerged as an important as an importantgroup of inborn group errors of inborn of metabolism errors of with metabolism clinical significance. with clinical significance.Affected patients Affected with patients mitochondrial with mitochondrial FAO defects FAO usually defects present usually in the present first inyear the of first life yearwith of a life withReye’s-like a Reye’s-like syndrome, syndrome, cardiomyopathy, cardiomyopathy, and andneur neuro-myopathy.o-myopathy. Death Death quic quicklykly ensue ensue unless unless the the disorderdisorder is rapidly is rapidly recognized recognized and and treated. treated. FigureFigure 1. Mitochondrial1. Mitochondrial fatty fatty acid acidβ β-oxidation-oxidation pathway.pathway. Classical Classical ββ-oxidation-oxidation pathway pathway involves involves dehydrogenasedehydrogenase by by acyl-CoA acyl-CoA dehydrogenase dehydrogenase andand hydration,hydration, dehydrogenation dehydrogenation and and thiolyic thiolyic cleavage cleavage is catalyzedis catalyzed by by the the mitochondrial mitochondrial trifunctional trifunctional proteinprotein (MTP, (MTP, highlighted highlighted in in red red color). color). MTP MTP consists consists of enoyl-CoAof enoyl-CoA hydratase, hydratase, hydroxy hydroxy acyl-CoA acyl-CoA dehydrog dehydrogenaseenase and thiolase and thiolase activity. activity. The straight The arrows straight arrowsrepresent represent products products and bent and arrows bent arrowsrepresent represent the involvement the involvement of co-factor of in co-factorthis enzyme in thiscatalyzed enzyme catalyzedreaction. reaction. 1.2. Peroxisomal and Microsomal Fatty Acid Oxidation 1.2. Peroxisomal and Microsomal Fatty Acid Oxidation In the event of defective mitochondrial β-oxidation due to a mutation in the β-oxidation enzymes,In the event long of chain defective fatty mitochondrialacids can be channeledβ-oxidation to peroxisomal due to a mutation β-oxidation in the andβ-oxidation microsomal enzymes, ω- longoxidation chain fatty [5,6]. acids Unlike can mitochondrial be channeled tofatty peroxisomal acid oxidation,β-oxidation peroxisomal and microsomalβ-oxidation !is -oxidationnot coupled [5 ,6]. Unlikewith mitochondrialthe mitochondrial fatty electron acid oxidation,transport ch peroxisomalain and ATP generation.β-oxidation Increased is not coupledperoxisomal with β- the mitochondrialoxidation would electron increase transport the production chain and of hydrog ATP generation.en peroxide as Increased a byproduct peroxisomal of the peroxisomalβ-oxidation wouldacyl-CoA increase oxidase, the production a rate-limiting of hydrogenenzyme and peroxide first step as of a peroxisomal byproduct ofβ-oxidation. the peroxisomal The rest acyl-CoAof the Int. J. Mol. Sci. 2018, 19, 322 3 of 17 oxidase, a rate-limiting enzyme and first step of peroxisomal β-oxidation. The rest of the peroxisomal β-oxidation pathway is similar to the mitochondrial β-oxidation pathway with the exception of the presence of a peroxisomal bifunctional protein, which contains an N-terminal peroxisomal enoyl-CoA hydratase and a C-terminal region that contains 3-hydroxy acyl-CoA dehydrogenase activity. Increased reactive oxygen species from the peroxisomal β-oxidation can lead to redox imbalance, mitochondrial dysfunction and cellular injury [7]. Further, accumulated fatty acids and 3-hydroxy fatty acids can also be shunted to the endoplasmic reticulum for microsomal !-oxidation. In the liver, peroxisome proliferator-activator receptor (PPAR)-α transcriptionally regulates genes that encodes for both peroxisomal β-oxidation and microsomal !-oxidation enzymes [6]. Enhanced microsomal !-oxidation of fatty acids and 3-hydroxy fatty
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