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

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: 3-hydroxy fatty acids; acute fatty liver of pregnancy; fatty acid oxidation; lipoapoptosis.

Figure 1

Mitochondrial fatty acid β-oxidation pathway. Classical β-oxidation pathway involves dehydrogenase by acyl-CoA dehydrogenase and hydration, dehydrogenation and thiolyic cleavage is catalyzed by the mitochondrial trifunctional protein (MTP, highlighted in red color). MTP consists of enoyl-CoA hydratase, hydroxy acyl-CoA dehydrogenase and thiolase activity. The straight arrows represent products and bent arrows represent the involvement of co-factor in this enzyme catalyzed reaction.

Figure 2

Schematic representation of the sequence of events that happen during acute fatty liver of pregnancy (AFLP). Fetal long chain 3-hydroxy acyl-CoA dehydrogenase (LCHAD) deficiency results in accumulation of 3-hydroxy fatty acids in the placenta, since the fetal part of placenta is identical to the genetic makeup of the fetus. Increased accumulation of placental free fatty acids and 3-hydroxy fatty acyl-CoA cause oxidative stress, mitochondrial dysfunction and placental lipotoxicity. Further, lipolysis induced in the third trimester of pregnancy would also trigger the accumulation of fatty acid intermediates, which are shunted from the placenta to the maternal circulation, where they can promote oxidative and nitrosative stress. These fatty acid intermediates reach the maternal liver resulting in microvesicular steatosis, hepatic mitochondrial dysfunction and hepatocyte lipoapoptosis.

Figure 3

Other complications due to 3-hydroxy fatty acid (3-HFA) accumulation. LCHAD deficiency in children results in docosahexenoic acid (DHA) deficiency and 3-HFA accumulation induces neuronal mitochondrial and oxidative damage in the brain. LCHAD deficiency was also associated with ocular abnormalities and retinal pigment epithelial cell lipoapoptosis. In the pancreas, 3-HFA alters mitochondrial bioenergetics in the islet β-cells.