Abstract
Non-alcoholic fatty liver disease (NAFLD) is an emerging global health problem and a potential risk factor for type 2 diabetes, cardiovascular disease, and chronic kidney disease. Nonalcoholic steatohepatitis (NASH), an advanced form of NAFLD, is a predisposing factor for development of cirrhosis and hepatocellular carcinoma. The increasing prevalence of NASH emphasizes the need for novel therapeutic approaches. Although therapeutic drugs against NASH are not yet available, fundamental insights into the pathogenesis of NASH have been made during the past few decades. Multiple therapeutic strategies have been developed and are currently being explored in clinical trials or preclinical testing. The pathogenesis of NASH involves multiple intracellular/extracellular events in various cell types in the liver or crosstalk events between the liver and other organs. Here, we review current findings and knowledge regarding the pathogenesis of NASH, focusing on the most recent advances. We also highlight hormone-based therapeutic approaches for treatment of NASH.
Highlights
The liver is a central metabolic organ that coordinates whole-body energy homeostasis by regulating glucose, lipid, and protein metabolism
non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH) is a public health problem worldwide, but there are no therapeutic drugs approved for its treatment
Numerous preclinical animal models based on genetic or dietary manipulation with relevance to human NAFLD/NASH have been developed to explore the mechanisms underlying the development of NAFLD/NASH and identify novel targets for its treatment [145, 146]
Summary
The liver is a central metabolic organ that coordinates whole-body energy homeostasis by regulating glucose, lipid, and protein metabolism. Numerous studies suggest that NASH develops by multiple intracellular/extracellular events in different liver cell types such as hepatocytes, hepatic stellate cells (HSCs), Kupffer cells (resident macrophages in the liver), and infiltrating macrophages [4] and by inter-organ crosstalk between the liver and other tissues including adipose tissue or the intestine [5, 6]. This “multiple-parallel hit” model has recently been considered as a more adequate hypothesis to understand the pathogenesis of NASH than the “two-hit” model in which hepatic steatosis, the “first hit,” increases susceptibility to NASH caused by a “second hit” such as oxidative stress and inflammatory cytokines [7]. We briefly describe the importance of the adipose tissue-liver axis and intestine-liver axis in the pathogenesis of NASH, emphasizing the most recent findings (Figure 1)
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