Liver injury in acute fatty liver of pregnancy: possible link to placental mitochondrial dysfunction and oxidative stress.
Acute fatty liver of pregnancy (AFLP) is a rare disorder which is fatal if not recognized and treated early. Delivery of the feto-placental unit results in dramatic improvement in maternal liver function, suggesting a role for the placenta. However, the mechanisms by which defects in the fetus or placenta lead to maternal liver damage are not well understood and form the focus of this study. Placenta and serum were obtained at delivery from patients with AFLP, and placental mitochondria and peroxisomes were isolated. Placental mitochondrial function, oxidative stress, and fatty acid composition as well as serum antioxidants, oxidative and nitrosative stress markers, and fatty acid analysis were carried out. Hepatocytes in culture were used to evaluate cell death, mitochondrial function, and lipid accumulation on exposure to fatty acids. Oxidative stress was evident in placental mitochondria and peroxisomes of patients with AFLP, accompanied by compromised mitochondrial function. Increased levels of arachidonic acid were also seen in AFLP placenta when compared to control. Patients with AFLP also had a significant increase in oxidative and nitrosative stress markers in serum, along with decreased antioxidant levels and elevated levels of arachidonic acid. These levels of arachidonic acid were capable of inducing oxidative stress in hepatocyte mitochondria accompanied by induction of apoptosis. Exposure to arachidonic acid also resulted in increased lipid deposition in hepatocytes.


CONCLUSIONS
Oxidative stress in placental mitochondria and peroxisomes is accompanied by accumulation of toxic mediators such as arachidonic acid, which may play a causative role in maternal liver damage seen in AFLP.
Natarajan
Sathish Kumar
SK
The Wellcome Trust Research Laboratory, Department of Gastrointestinal Sciences, Vellore, India.
Thangaraj
Kavitha R
KR
Eapen
C E
CE
Ramachandran
Anup
A
Mukhopadhya
Ashis
A
Mathai
Mathews
M
Seshadri
Lakshmi
L
Peedikayil
Abraham
A
Ramakrishna
Banumathi
B
Balasubramanian
Kunnissery A
KA
D000975:Antioxidants / Q000378:metabolism; D005234:Fatty Liver / Q000378:metabolism*; D005260:Female; D006801:Humans; D008928:Mitochondria / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D010920:Placenta / Q000378:metabolism*; D011247:Pregnancy; D011248:Pregnancy Complications / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism
D000975:Antioxidants; D017382:Reactive Oxygen Species