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Oxidized LDL

Oxidized LDL and NAFLD/NASH

Oxidative stress is an important pathological event in the progression of NAFLD towards NASH1,2, and levels of OxLDL has been shown to be increased in NASH compared with controls3.

The role of OxLDL is far from fully understood, but several studies have demonstrated a relationship between NAFLD/NASH and oxLDL. In 2008 it was shown that a postprandial increase in oxLDL independently predicted the severity of liver histology in subjects with NAFLD. The authors suggested that oxLDL could be a biological mechanism for the epidemiological association between liver disease and atherosclerosis in NASH4.

In the liver, oxLDL gets trapped inside lysosomes of Kupfer cells, which is liver specific macrophages, leading to increased hepatic inflammation and inflammatory gene expression5.

In a high fat diet (HFD) mouse model, oxLDL administration aggravated the hepatic steatosis, the fibrosis, and also resulted in intense inflammation and severe hepatic injury, which are the typical histological features of NASH. These results suggest that an increased oxidative state, including HFD-induced intracellular lipid peroxidation and its extracellular source from oxLDL, is the actual trigger for hepatic inflammation in which liver injury is mediated6.

The involvement of oxLDL in NASH indeed needs further investigation according to a Dutch research group that states “Despite the relationship between oxLDL and liver steatosis, further studies are clearly needed to assess the clinical adequacy of plasma oxLDL as a noninvasive biomarker for NASH and to provide a basis for therapeutic strategies to improve NASH and related metabolic risk factors that conduct to T2D, cardiovascular diseases, and liver deterioration”1.
 

References

1.            Walenbergh, S. M. A., Koek, G. H., Bieghs, V. & Shiri-Sverdlov, R. Non-alcoholic steatohepatitis: The role of oxidized low-density lipoproteins. J. Hepatol. 58, 801–810 (2013).

2.          Spahis, S., Delvin, E., Borys, J.-M. & Levy, E. Oxidative Stress as a Critical Factor in Nonalcoholic Fatty Liver Disease Pathogenesis. Antioxid. Redox Signal. 26, 519–541 (2017).

3.           Chalasani, N., Deeg, M. A. & Crabb, D. W. Systemic levels of lipid peroxidation and its metabolic and dietary correlates in patients with nonalcoholic steatohepatitis. Am J Gastroenterol 99, 1497–1502 (2004).

4.           Musso, G. et al. Association of liver disease with postprandial large intestinal triglyceride-rich lipoprotein accumulation and pro/antioxidant imbalance in normolipidemic non-alcoholic steatohepatitis. Ann. Med. 40, 383–394 (2008).

5.           Bieghs, V. et al. Trapping of oxidized LDL in lysosomes of Kupffer cells is a trigger for hepatic inflammation. Liver Int. 33, 1056–61 (2013).

6.           Yimin et al. A novel murine model for non-alcoholic steatohepatitis developed by combination of a high-fat diet and oxidized low-density lipoprotein. Lab. Invest. 92, 265–81 (2012).