New Insights into the Pathogenesis of Non-Alcoholic Fatty Liver Disease: Gut-Derived Lipopolysaccharides and Oxidative Stress

Abstract

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide. The intricate NAFLD pathogenesis is summarized by the multiple-hits hypothesis, which combines all the environmental and genetic factors that promote the development of NAFLD into a single scenario. Among these, bacterial lipopolysaccharides (LPS) are derived from the overgrowth of Gram-negative bacteria and translocated mainly as a consequence of enhanced intestinal permeability. Furthermore, oxidative stress is increased in NAFLD as a consequence of reactive oxygen species (ROS) overproduction and a shortage of endogenous antioxidant molecules, and it is promoted by the interaction between LPS and the Toll-like receptor 4 system. Interestingly, oxidative stress, which has previously been described as being overexpressed in cardiovascular disease, could represent the link between LPS and the increased cardiovascular risk in NAFLD subjects. To date, the only effective strategy for the treatment of NAFLD and non-alcoholic steatohepatitis (NASH) is the loss of at least 5% body weight in overweight and/or obese subjects. However, the dose-dependent effects of multispecies probiotic supplementation on the serum LPS level and cardiometabolic profile in obese postmenopausal women were demonstrated. In addition, many antibiotics have regulatory effects on intestinal microbiota and were able to reduce serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), and tumor necrosis factor alpha (TNF-α) in NASH animal models. Regarding the oxidant status, a Mediterranean diet has been reported to reduce oxidant stress, while vitamin E at high daily dosages induced the resolution of NASH in 36% of treated patients. Silymarin had the positive effect of reducing transaminase levels in NAFLD patients and long-term treatment may also decrease fibrosis and slow liver disease progression in NASH. Finally, the influence of nutraceuticals on gut microbiota and oxidant stress in NAFLD patients has not yet been well elucidated and there are insufficient data either to support or refuse their use in these subjects.

Pediatric Non-Alcoholic Fatty Liver Disease: Nutritional Origins and Potential Molecular Mechanisms

“…Oxidative stress plays a key role in the pathogenesis of NAFLD and progression to NASH (reviewed recently in [79]). Nobili et al [80] found that oxidative stress is highly prevalent in pediatric NAFLD.…”

Role and Mechanisms of Probiotics in Regulating the ROS/JNK Signaling Pathway in the Pathogenesis of Nonalcoholic Fatty Liver Disease.

“…On the one hand, the endotoxins entering the blood circulation not only directly damage the intestinal mucosal epithelial cells, but also induce intestinal microvasculature contractions and intestinal tissue ischemia and hypoxia, leading to excessive ROS production. Meanwhile, the increase in the intestinal permeability augments endotoxin absorption, which is also a huge burden on the liver (28,29). On the other hand, because of the presence of the intestine-liver axis, the endotoxins entering the blood circulation also act directly on the liver, causing its in ammation by activating Toll-like receptors (29)(30)(31).…”

“…Meanwhile, the increase in the intestinal permeability augments endotoxin absorption, which is also a huge burden on the liver (28,29). On the other hand, because of the presence of the intestine-liver axis, the endotoxins entering the blood circulation also act directly on the liver, causing its in ammation by activating Toll-like receptors (29)(30)(31).…”

Nutrition Strategy and Life Style in Polycystic Ovary Syndrome—Narrative Review

“…Ultimately, in advanced PCOS with accompanying disease associated with metabolic syndrome and the steatosis of internal organs (especially non-alcoholic fatty liver disease), herbs and their extracts with proven properties should be considered for their hepatoprotective activities [ 136 ]. These substances include the silymarin contained in milk thistle ( Silybum marianum ) [ 137 , 138 ] and sesquiterpenes and antioxidant-active ingredients in artichoke ( Cynara Cardunculus ) extract [ 139 , 140 ].…”