Localization of oxidized phosphatidylcholine in nonalcoholic fatty liver disease: Impact on disease progression

Abstract

Nonalcoholic steatohepatitis/nonalcoholic fatty liver disease is considered to be a hepatic manifestation of various metabolic disorders. However, its precise pathogenic mechanism is obscure. Oxidative stress and consequent lipid peroxidation seem to play a pivotal role in disease progression. In this study, we analyzed the localization of oxidized phosphatidylcholine (oxPC), a lipid peroxide that serves as a ligand for scavenger receptors, in livers of patients with this steatotic disorder. Specimens of nonalcoholic fatty liver disease (15 autopsy livers with simple steatosis and 32 biopsy livers with steatohepatitis) were examined via immunohistochemistry and immunoelectron microscopy using a specific antibody against oxPC. In addition, scavenger receptor expression, hepatocyte apoptosis, iron deposition, and inflammatory cell infiltration in the diseased livers were also assessed. Oxidized phosphatidylcholine was mainly localized to steatotic hepatocytes and some macrophages/Kupffer cells. A few degenerative or apoptotic hepatocytes were also positive for oxPC. Immunoelectron microscopy showed oxPC localized to cytoplasmic/intracytoplasmic membranes including lipid droplets. Steatotic livers showed enhanced expression of scavenger receptors. The number of oxPC cells was correlated with disease severity and the number of myeloperoxidasepositive neutrophils, but not with the degree of iron deposition. In conclusion, distinct localization of oxPC in liver tissues suggest that neutrophil myeloperoxidase-derived oxidative stress may be crucial in the formation of oxPC and the progression of steatotic liver disease. (HEPATOLOGY 2006;43:506-514.)

Silybin combined with phosphatidylcholine and vitamin E in patients with nonalcoholic fatty liver disease: A randomized controlled trial

“…ERK-, MEK-, and mitogenactivated protein kinase-related pathways are regulated and regulate Jun N-terminal kinase (JNK) expression, which has a pivotal role in obesity and insulin resistance [52]. Phosphatidylcholine, another component of the RA preparation, protects against oxidative stressmediated liver damage [53,54]. It is unlikely that the treatment effects are related to the vitamin E component, which is much lower (60 IU/ day) than doses with documented efficacy [4].…”

Oxidative stress parameters in paediatric non-alcoholic fatty liver disease

“…Previous studies have shown that the intra-hepatic detection of lipid peroxidation products is prevalent in patients with NASH and correlates with necro-inflammation (11)(12)(13). Several lines of evidence in ALD indicate the involvement of immunological mechanisms in fuelling hepatic inflammation during the progression of the disease (27).…”

“…Accordingly, antioxidant supplementation reduces liver injury in experimental rodent models of NASH (9,10). The relevance of these observations in humans is supported by several studies showing increased liver and serum content of oxidative stress markers, such as lipid peroxidation end-products, 8-hydroxy-2-deoxyguanosine (8-OHG), and nitrotyrosine in adult patients with NAFLD/ NASH (11)(12)(13). Moreover, microarray analysis of liver biopsies from patients with NASH demonstrated lower mRNA expression of different antioxidant enzymes (14).…”

Ultrastructural findings in human nonalcoholic steatohepatitis

“…The droplet serves as a means of safely storing fatty acids as triglyceride or exporting them through lipid transfer from the droplet to nascent very-low-density lipoproteins. Fat droplets are also targets for key regulatory hormones, including insulin, glucagon and epinephrine, through activity of fat droplet-associated surface perilipin/ADRP/TIP47 (PAT) proteins, which regulate lipase activity on the neutral lipid within the droplet [38][39][40]. Oxidative injury to the phospholipid monolayer around the droplets, altered expression of PAT in NASH and the interaction of droplets with cytoskeletal elements suggests that dysfunction of these organelles may be central to NASH pathogenesis [41][42][43][44][45][46].…”