Lessons from animal models of NASH
Introduction
The purpose of this session is to update understanding about the pathogenesis of NASH by reviewing information that has been generated from animal models of NASH. NASH is an important type of liver disease because it is an intermediary stage of liver pathology that develops as fatty liver disease progresses to cirrhosis and hepatocellular carcinoma. In humans, NASH is associated with the metabolic syndrome, i.e., obesity, diabetes, dyslipidemia and insulin resistance [1]. Therefore, the ideal animal models of NASH also manifest these conditions.
This summary will emphasize advances that have resulted from the realization that factors derived from adipose tissue play major roles in the pathogenesis of NASH. Indeed, this should not be surprising because it is generally acknowledged that NASH is strongly associated with obesity in humans [2]. Studies in obese animals are beginning to clarify why fat promotes NAFLD. The data demonstrate that adipose tissue is not merely an inert depot that stores triglyceride that is released from the liver. Nor is it simply a source of free fatty acids that are delivered to the liver. Rather, fat tissue is an important contributor to the metabolic syndrome because it makes various hormones, as well as different cytokines [3]. These fat-derived factors mediate the development NAFLD, the liver disease that is associated with the metabolic syndrome.
Section snippets
Adipose tissue promotes the metabolic syndrome and NAFLD
In the metabolic syndrome, adipose tissue is a source of several factors that promote the development of liver disease [1], [3]. For example, free fatty acids that are released from fat tissue play an important role in the pathogenesis of the insulin resistance, metabolic syndrome and NASH. Below, we summarize evidence that demonstrates how fatty acids contribute to the pathogenesis of hepatic insulin resistance.
Progression from NAFL to NASH
Initial efforts to clarify the mechanisms that promote the progression from steatosis to steatohepatitis somewhat artificially divided disease mechanisms into “first” and “second” hits [15]. As research has progressed, it has become more evident that these “hits” are not always discrete events. Rather, initial and subsequent mechanisms blend into each other. For example, the second “hit” that drives progression to steatohepatitis may be ongoing in individuals with simple hepatic steatosis, but
Progression from NASH to cirrhosis
The next question that needs to be addressed is what causes some individuals with steatohepatitis to develop cirrhosis? Human studies tell us that cirrhosis occurs more often in people with NASH than in those with simple fatty liver [36]. We have also learned that most cases of cryptogenic cirrhosis occur in individuals who have risk factors for NASH [37]. Therefore, it seems that steatohepatitis is an important precursor of cirrhosis. On the other hand, however, we know that most people with
NAFLD and hepatocellular carcinoma
Finally, it is important to discuss the impact of chronic liver injury on liver repair, because of growing evidence that NAFLD may be complicated by hepatocellular cancer [49]. Interestingly, although liver cancer in humans rarely occurs in the absence of cirrhosis, many of the animal models of NASH that do not develop cirrhosis do develop hepatocellular carcinomas [39]. Initially, this was confusing to us because our work clearly demonstrated that mature hepatocytes become replicatively
Conclusions
In summary, various animal models are informative because they accurately model what seems to occur in people. Specifically, in many obese animals and humans with the metabolic syndrome and NASH, there is an excessive production of TNF relative to adiponectin. This imbalance promotes a state of chronic oxidative stress that enhances liver cell death. The latter is not sufficient to cause progressive NASH because most mice and humans compensate for chronic oxidative stress by up-regulating
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2019, Biochimica et Biophysica Acta - Molecular Basis of DiseaseCitation Excerpt :TNF-α may be produced by Kupffer cells, adipose tissue, hepatocytes, stellate cells, monocytes, neutrophils, dendritic cells and natural killer cells [38,153]. Moreover, dietary factors modulate the intestinal microbiome, and the hepatic immune system is exposed to gut-derived inflammatory mediators resulting from increased gut permeability in patients with NAFLD as well as in animal models [13,33,36,153]. In several rodent NASH models the Hh signaling pathway is activated, as indicated by increased numbers of Hh-producing cells, and promotes liver inflammation through osteopontin (OPN)-mediated macrophage activation [8,154,155].
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