Obesity increases sensitivity to endotoxin liver injury: Implications for the pathogenesis of steatohepatitis

Abstract

Genetically obese fatty͞fatty rats and obese͞ obese mice exhibit increased sensitivity to endotoxin hepatotoxicity, quickly developing steatohepatitis after exposure to low doses of lipopolysaccharide (LPS). Among obese animals, females are more sensitive to endotoxin liver injury than males. LPS induction of tumor necrosis factor ␣ (TNF␣), the proven affecter of endotoxin liver injury, is no greater in the livers, white adipose tissues, or sera of obese animals than in those of lean controls. Indeed, the lowest serum concentrations of TNF occur in female obese rodents, which exhibit the most endotoxin-induced liver injury. Several cytokines that modulate the biological activity of TNF are regulated abnormally in the livers of obese animals. After exposure to LPS, mRNA of interferon ␥, which sensitizes hepatocytes to TNF toxicity, is overexpressed, and mRNA levels of interleukin 10, a TNF inhibitor, are decreased. The phagocytic activity of liver macrophages and the hepatic expression of a gene encoding a macrophage-specific receptor are also decreased in obesity. This new animal model of obesity-associated liver disease demonstrates that hepatic macrophage dysfunction occurs in obesity and suggests that this might promote steatohepatitis by sensitizing hepatocytes to endotoxin.

Mitochondrial dysfunction and oxidative stress in the pathogenesis of alcohol- and obesity-induced fatty liver diseases

“…As mentioned above, up-regulation of UCPs as an adaptive response to obesity results in hepatocyte ATP depletion when energy needs are acutely increased. Importantly, these studies demonstrated that hepatic necrosis occurred only when mitochondrial electron transport was inhibited [51,54]. Similarly, Diehl and colleagues demonstrated using 31 P NMR spectroscopy that recovery from hepatic ATP depletion is severely impaired in NASH patients [56] suggesting a NASH dependent bioenergetic defect.…”

“…Thus, it has been proposed that up-regulation of UCPs negatively impacts cellular energy conservation only when the availability of oxidizable substrates becomes limited, e.g. under conditions of acute stress like ischemia, partial hepatectomy, and lipopolysaccharide exposure [51,54,55]. Based on this information, further studies are required to elucidate the impact of obesity on hepatic mitochondrial physiology in vivo particularly in the context of whether mitochondria are coupled or un-coupled as a consequence of steatosis.…”

C3H/HeJ mice carrying a toll-like receptor 4 mutation are protected against the development of insulin resistance in white adipose tissue in response to a high-fat diet

“…Genetically obese rodents quickly develop steatohepatitis after exposure to low doses of LPS [12], while polymyxin B diminishes hepatic steatosis during total parenteral nutrition in the rat by reducing caecal flora [13]. Moreover, endotoxins exert a strong effect on liver of mice fed a high-fat diet [14].…”

Augmentation of 11β‐hydroxysteroid dehydrogenase type 1 in LPS‐activated J774.1 macrophages – Role of 11β‐HSD1 in pro‐inflammatory properties in macrophages

“…Recent studies highlighted the concept that not only LPS but non-microbial molecules such as fatty acids can also activate macrophages through TLR4 [21]. It is also suggested that endogenous, intestine-derived LPS contributes to the pathophysiology of obesity-associated fatty liver diseases [22]. In this context, potential mechanism of LPS-mediated dysfunction of adipose tissue stimulates much interest in future studies.…”

“…Macrophages play pathophysiologic roles in adipose dysfunction, arteriosclerosis [16] and inflammatory fatty liver diseases [22]. A recent study showed that pharmacologic inhibition of 11b-HSD1 ameliorated diabetes, dyslipidemia [29] and arteriosclerosis [16] in mouse models.…”