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Homi Bhabha National Institute, Training School Complex, Anushaktinagar, Mumbai, India
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Homi Bhabha National Institute, Training School Complex, Anushaktinagar, Mumbai, India
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Homi Bhabha National Institute, Training School Complex, Anushaktinagar, Mumbai, India
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Homi Bhabha National Institute, Training School Complex, Anushaktinagar, Mumbai, India
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Nonalcoholic fatty liver disease or NAFLD is a complex and multifactorial liver disease that is affecting a majority of the world’s population now more than ever. The review focuses on two major contributing factors in the etiology of the disease – oxidative stress and the gut microbiota. There is a complex interplay between oxidative stress and the gut microbiota in the pathogenesis of NAFLD. Oxidative stress in NAFLD can result from both the accumulation of lipids in the liver and the interactions between gut-derived metabolites and the liver. Dysbiosis in the gut microbiota can contribute to oxidative stress by promoting the production of reactive oxygen species and altering the balance of antioxidant systems. This interplay between oxidative stress and the gut microbiota can create a vicious cycle, where dysbiosis contributes to oxidative stress, and oxidative stress further promotes dysbiosis, exacerbating liver damage in NAFLD. Understanding the intricate relationship between oxidative stress, the gut microbiota, and NAFLD is essential for developing targeted therapeutic strategies. In this context, more scientific research is required to unravel the complex and interconnecting pathways underlying NAFLD pathogenesis and progression. Modulating the gut microbiota through dietary interventions, prebiotics, probiotics, and change in lifestyle may help restore microbial balance and reduce oxidative stress in NAFLD.
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Graphical Abstract
Abstract
Objective
Nonalcoholic steatohepatitis is a chronic liver disease caused by the progression of hepatocellular death and inflammation from simple steatosis. However, the pathogenesis of this disease remains unclear. Lipid peroxidation is one of the most critical factors in the development of nonalcoholic steatohepatitis; however, oxidised lipids – the products of lipid peroxidation – are insufficiently analysed. Here, we comprehensively analysed oxidised lipids in the liver during nonalcoholic steatohepatitis development in a choline-deficient, l-amino acid-defined, high-fat diet-fed mouse model.
Methods
Liver from C57BL/6J mice, fed a standard diet or a choline-deficient l-amino acid-defined high-fat diet for 1, 3, or 6 weeks, were collected to evaluate fibrosis, steatosis, inflammation, liver injury, and oxidised lipid production and to observe the suppression of these parameters upon vitamin E administration. In addition, organellar localisation of lipid peroxidation was assessed using fluorescence imaging. Finally, a mitochondria-targeted antioxidant was administered to model mice to investigate the mechanism underlying lipid peroxidation.
Results
We found an accumulation of oxidised triglycerides in the early stages of nonalcoholic steatohepatitis. Furthermore, our data indicate that oxidised triglycerides are generated by lipid peroxidation in lipid droplets due to mitochondria-derived reactive oxygen species.
Conclusion
These results suggest the importance of lipid droplet peroxidation in the progression of nonalcoholic steatohepatitis and may contribute to the development of therapeutic methods for nonalcoholic steatohepatitis in the future.
Significance statement
We demonstrate the specific and early occurrence of lipid peroxidation in nonalcoholic steatohepatitis pathogenesis and propose a previously unknown mechanism of disease progression.
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In the last decade, non-alcoholic fatty liver disease (NAFLD) and particularly its evolution to nonalcoholic steatohepatitis (NASH) have become a leading cause of chronic liver disease and cirrhosis as well as an important risk factor for hepatocellular carcinoma. Oxidative stress is a common feature of NAFLD/NASH and plays a key role in the complex of metabolic and cellular derangements that are involved in the development of liver steatosis, as well as in the transition to steatohepatitis. This review deals with the contribution of oxidative stress in promoting hepatic inflammation which represents a key factor in NAFLD evolution to liver fibrosis/cirrhosis. We discuss in detail recent data involving oxidative stress products as triggers for hepatic innate immunity and as a source of antigens implicated in sustaining lymphocyte-mediated adaptive immune responses. Attention is also paid to emerging evidence linking oxidative stress and extra-hepatic complications of NAFLD/NASH.
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The liver is characterized by unique regenerative properties to restore its mass and function after a partial loss. Hepatic regeneration arises after resection or following acute and chronic injuries. Resection and acute liver damage normally induce a regenerative process characterized by phenotypic fidelity, in which each cell type promotes its own replication and replacement. This process fails in chronic liver damage, where trans-differentiation of parenchymal cells or activation of facultative progenitors occurs. Both liver resection and acute/chronic damages alter redox homeostasis, as a consequence of blood flow changes, hypoxia, metabolism modification, and activation of inflammatory response. Even though formerly described as ‘oxidative stress’, altered redox homeostasis leads to the fine regulation of several pathways involved in liver regeneration, including the proliferation of parenchymal cells, trans-differentiation, and activation of facultative progenitors.
Several redox-dependent transcription factors and pathways implicated in the regenerative process of the liver were described, but pre-clinical experiments using different antioxidants were not fully conclusive. Even though accurate study designs to define appropriate dosages, treatment duration, and routes of administration are required, modulation of redox-dependent molecular pathways to enhance liver regeneration is even more intriguing. Preliminary studies focused on the identification of these targets will pave the way for viable therapies to be tested in clinical trials.
