Beyond insulin resistance in NASH: TNF-? or adiponectin?

Abstract

Adiponectin has antilipogenic and anti-inflammatory effects, while tumor necrosis factor ␣ (TNF-␣) reduces insulin sensitivity and has proinflammatory effects. We examined (1) the extent to which hypoadiponectinemia and TNF-␣ activation are features of nonalcoholic steatohepatitis (NASH) and (2) whether serum levels of these markers correlate with the severity of histological changes in 109 subjects with nonalcoholic fatty liver disease (NAFLD), including 80 with NASH and 29 with simple steatosis. By multivariate analysis, subjects with NASH had reduced adiponectin level and increased TNF-␣ and soluble TNF receptor 2 (sTNFR2)-but not leptin levels, compared with controls matched by age, sex, and body mass index; these differences were independent of the increased insulin resistance (by homeostasis model [HOMA-IR]) in NASH. When compared with simple steatosis, NASH was associated with lower adiponectin levels and higher HOMA-IR, but there were no significant differences in the levels of TNF-␣ and sTNFR2. The majority of subjects with steatohepatitis (77%) had adiponectin levels less than 10 g/mL and HOMA-IR greater than 3 units, but only 33% of those with pure steatosis had these findings. HOMA-IR and low serum adiponectin were also independently associated with increased grades of hepatic necroinflammation. In conclusion, hypoadiponectinemia is a feature of NASH independent of insulin resistance. Reduced adiponectin level is associated with more extensive necroinflammation and may contribute to the development of necroinflammatory forms of NAFLD. (HEPATOLOGY 2004;40:46 -54.)

Metabolic profiles in patients with chronic hepatitis C: a case–control study

“…Our findings showed the existence of a close link between HCV infection and metabolic abnormalities. We found that HCV infection was positively correlated with serum adiponectin level, which was different from previously reports on subjects with non-alcoholic steatohepatitis (NASH) [20,33].…”

“…Adiponectin, an adipokine, has been implicated in the pathogenesis of type 2 diabetes mellitus and nonalcoholic fatty liver disease (NAFLD), and appears to have many favorable effects on glucose and lipid metabolism [20,21]. It is positively correlated with insulin sensitivity and is decreased in obese and type 2 diabetic patients [22].…”

Increased risk of cardiovascular disease in non-alcoholic fatty liver disease: causal effect or epiphenomenon?

“…Patients with NAFLD exhibit reduced adiponectin levels, which are inversely correlated with the severity of NAFLD histology [59]. The reduced production of adiponectin associated with obesity may contribute to the progression of NAFLD [46,56,59] and CVD [60], since this hormone appears to exert strong anti-inflammatory and anti-fibrotic effects. In contrast, leptin levels are increased in NAFLD, and may play a role in the progression from pure steatosis to NASH, at least according to studies in animal models [46,56].…”

Hypertension and fatty liver: guilty by association?

“…It is unclear how the 'second hit' leads to the development of progressive liver disease, although oxidative stress and pro-inflammatory cytokines have been implicated. [56][57][58] The nature of these 'hits' is unknown.…”

“…61 Serum and hepatic adiponectin levels are lower in patients with NASH than in those with simple steatotsis. 56,62 It has also been shown that exogenous adiponectin reverses experimental NAFLD and NASH, potentially via peroxisome proliferator-activated receptor-a (PPAR-a). 63 This is supported by evidence that thiazolidinediones (which are PPAR-g agonists) stimulate adiponectin synthesis and are a potential therapeutic agent in fatty liver disease.…”