New Insights into the Pathogenesis of Non-Alcoholic Fatty Liver Disease: Gut-Derived Lipopolysaccharides and Oxidative Stress - PubMed (original) (raw)

Review

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

Domenico Ferro et al. Nutrients. 2020.

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.

Keywords: cardiovascular risk; lipopolysaccharide; non-alcoholic fatty liver disease; oxidative stress.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1

The role of increased serum lipopolysaccharides (LPS) and oxidative stress in the pathogenesis of non-alcoholic fatty liver disease. Dysmetabolic conditions, such as obesity, metabolic syndrome, and type 2 diabetes may induce oxidative stress as a consequence of increased insulin resistance, low-grade inflammation, and a reduction in antioxidants. Bacterial overgrowth, excessive alcohol consumption, and a diet rich in fat may induce increased intestinal LPS translocation. Oxidative stress and LPS promote hepatocellular damage, as well as hepatic stellate cell and Kupfer cell activation. PNPLA3: Patatin-like phospholipase domain-containing protein 3; Nox: NADPH oxidase; M1: M1 macrophages; ROS: Reactive oxygen species; HSC: Hepatic stellate cell; KC: Kupfer cell; TLR4: Toll-like receptor 4; pNF-κB: Phosphorylated nuclear factor κB; TNF-α: Tumor necrosis factor α; IL-6: interleukin 6; TGFβ: Transforming growth factor β.

Figure 2

Possible effects of LPS in non-alcoholic fatty liver disease and non-hepatic disorders.

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New Insights into the Pathogenesis of Non-Alcoholic Fatty Liver Disease: Gut-Derived Lipopolysaccharides and Oxidative Stress - PubMed (original) (raw)