Mechanism of NAFLD/NASH
Despite the high prevalence rates, a precise understanding of the environmental and genetic factors that lead to NAFLD and NASH remains poorly defined. Several investigators presented data that may inform the issue.
The Role of the Innate Humoral Immune Response
Karrar and collegues postulated that ficolins are involved in the pathogenesis of steatosis. H-ficolin and L-ficolin are acute-phase proteins/lectins that activate the complement system (humoral innate immunity).
Patients with histologic NASH had significantly higher serum levels of H-ficolin. In fact, levels of H-ficolin positively correlated with individual histologic features of NASH (steatosis, inflammatory cells, ballooning, and fibrosis) and with body mass index (BMI). This may indicate that H-ficolin plays an immunomodulatory role in the pathogenesis of NASH.
NAFLD is associated with high serum levels of triglycerides and low-density lipoprotein cholesterol, and low levels of high-density lipoprotein cholesterol. Because NAFLD and blood lipid levels are genetically influenced and may share a common genetic etiology, Puentes and colleagues identified genes and pathways enriched for genetic associations with both lipids in serum and steatosis, using human genome-wide association study data. They found an association with human genetic variation in or near the genes involved in FXR/RXR activation, suggesting that genes that play a role in bile acid, cholesterol, and lipid metabolism, when altered, may affect NAFLD. This could provide possible therapeutic targets for NAFLD prevention or treatment.
ApoA5, expressed exclusively in the liver, plays a key role in plasma triglycerides homeostasis. Wang and colleagues hypothesized that ApoA5 deficiency would perturb the balance of daily input and output of fatty acids in the liver. ApoA5 deficiency in chow-fed mice led to spontaneous development of NAFLD. This gradually evolved from simple steatosis to NASH and subsequently to liver fibrosis, which closely recapitulates the process of NAFLD in humans.
These innovative studies provide insight into the mechanisms underlying the role of lipid and ApoA5 metabolism in the pathogenesis of NAFLD and provide novel targets for pharmacologic intervention.
Medscape Gastroenterology © 2014 WebMD, LLC
Cite this: William F. Balistreri. Advances in Liver Disease - Medscape - Jun 19, 2014.