Mechanisms Involved in Tumor Necrosis Factor-α Induction of Insulin Resistance and Its Reversal by Thiazolidinedione(s)

Solomon, Solomon S.; Usdan, Lisa S.; Palazzolo, Marjorie

doi:10.1097/00000441-200108000-00005

Cited by 13 publications

(7 citation statements)

References 18 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…TNF-α is an important mediator of insulin resistance in obesity and diabetes through its ability to decrease the tyrosine kinase activity of the insulin receptor (Hotamisligil et al, 1996). The study conducted by Solomon et al(2001) proved that TZDs can reverse the insulin resistance induced by TNF-α. In this study, the level of TNF-α in model group I was significantly higher than that of control group I, the level of TNF-α in model group II also had increasing tendency, the level of TNF-α in PGZ treatment group was significantly lower than that of model group II.…”

Section: Discussionmentioning

confidence: 99%

Research on the protection effect of pioglitazone for non-alcoholic fatty liver disease (NAFLD) in rats

Zhang

et al. 2006

J. Zhejiang Univ. - Sci. B

View full text Add to dashboard Cite

Abstract:Objective: The prevalence of non-alcoholic fatty liver disease (NAFLD) has markedly increased. Insulin resistance has been implicated in the pathogenesis of NAFLD. This study was aimed at observing the relationship between insulin resistance and NAFLD, and evaluating the role of pioglitazone (PGZ) acting as insulin-sensitizing agents in the prevention and treatment of rat fatty liver induced by high fat feeding. Methods: The rats were separated randomly into 6 groups: model group I were fed high fat diet for 8 weeks, PGZ prevention group were given PGZ 4 mg/(kg⋅d) simultaneously, while control group I were fed normal food for 8 weeks; model group II were fed high fat diet for 16 weeks, PGZ treatment group were given PGZ 4 mg/(kg⋅d) orally simultaneous with high fat diet for 8 weeks after high fat feeding for 8 weeks, control group II were fed normal food for 16 weeks. The rats were sacrificed after 8 weeks and 16 weeks respectively. Liver weight, body weight, serum activities of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), tumor necrosis factor alpha (TNF-α), fasting blood glucose (FBG), fasting plasma insulin (FINS), HOMA (homeostasis model assessment) insulin resistance index (HOMA-IR), and the liver histology of rats of all groups were assayed. Results: After 8 weeks, the liver in model group I showed typical steatosis, accompanied with mild to moderate lobular inflammatory cell infiltration, liver indexes and serum levels of ALT, AST, ALP, TNF-α were significantly increased (P<0.05) compared with control group I. Whereas, the degree of hepatic injury was attenuated in PGZ prevention group, liver indexes and serum levels of ALT, ALP were significantly decreased (P<0.05) compared with model group I. After 16 weeks, notable steatosis, and lobular inflammation were observed in model group II rat liver, while the degree of hepatic injury was attenuated in the PGZ treatment group. Liver index, serum levels of ALT, AST, ALP, FINS and HOMA-IR were significantly increased (P<0.05) in model group II compared with control group II. Whereas, in PGZ treatment group, serum levels of AST and FINS showed decreasing tendency, liver indexes, serum levels of ALT, ALP, TNF-α and HOMA-IR were significantly decreased compared with model group II. Conclusion: Insulin resistance plays a role in the pathogenesis of NAFLD in rats. Pioglitazone can attenuate insulin resistance and biochemical and histological injury in high fat-induced fatty liver in rats.

show abstract

Section: Discussionmentioning

confidence: 99%

Research on the protection effect of pioglitazone for non-alcoholic fatty liver disease (NAFLD) in rats

Zhang

et al. 2006

J. Zhejiang Univ. - Sci. B

View full text Add to dashboard Cite

show abstract

“…7 Adipose tissue and circulating TNF-a levels are elevated in dietary obesity and lead to insulin resistance. TNF-a promotes the development of hepatic steatosis by increasing lipogenic gene expression, 60 and pharmacologic or genetic inhibition of TNF-a signaling is associated with decreased hepatic steatosis. 61,62 An apoptotic role for TNF-a in human NASH has not been observed.…”

Section: Death Receptorsmentioning

confidence: 99%

Molecular Mechanisms of Lipotoxicity in Nonalcoholic Fatty Liver Disease

Malhi

Gores²

2008

Semin Liver Dis

473

404

View full text Add to dashboard Cite

Nonalcoholic fatty liver disease (NAFLD) is characterized by insulin resistance, which results in elevated serum concentration of free fatty acids (FFAs). Circulating FFAs provide the substrate for triacylglycerol formation in the liver, and may also be directly cytotoxic. Hepatocyte apoptosis is a key histologic feature of NAFLD, and correlates with progressive inflammation and fibrosis. The molecular pathways leading to hepatocyte apoptosis are not fully defined; however, recent studies suggest that FFA-induced apoptosis contributes to the pathogenesis of nonalcoholic steatohepatitis. FFAs directly engage the core apoptotic machinery by activating the proapoptotic protein Bax, in a c-jun N-terminal kinase-dependent manner. FFAs also activate the lysosomal pathway of cell death and regulate death receptor gene expression. The role of ER stressand oxidative stress in the pathogenesis of nonalcoholic steatohepatitis has also been described. Understanding the molecular mediators of liver injury should promote development of mechanism-based therapeutic interventions. KeywordsBim; c-jun N-terminal kinase; oleic acid; palmitic acid; hepatocyte injury Lipotoxicity is loosely defined as cellular toxicity observed in the presence of an abnormal accumulation of fat. 1 Fat accumulation in the liver or hepatic steatosis is a morphologic feature of myriad conditions. This review focuses on the known mechanisms of cellular toxicity secondary to obesity-related fatty liver. Adipose tissue serves as the primary repository of caloric excess and undergoes numerous functional changes that characterize the obese, 2,3 insulin resistant, adipocyte; starkly absent among these changes, especially in comparison to other target tissues, is adipocyte apoptosis. These adipocyte changes include enhanced lipolysis with release of free fatty acids [also known as nonesterified fatty acids (NEFA)], 4 release of adipokines 5,6 and inflammatory cytokines. 7 These perturbations along with hepatocellular insulin resistance promote the development of hepatocyte steatosis, a condition recognized as nonalcoholic fatty liver disease (NAFLD). In NAFLD progressive triacylglycerol deposition exceeds the livers capacity to export very low-density lipoprotein particles (VLDL) and β-oxidation of free fatty acids (FFAs). Furthermore, a proportion of patients with NAFLD develop hepatic inflammation, known as nonalcoholic steatohepatitis (NASH), and can progress to cirrhosis with all its attendant complications. 8 HEPATIC LIPIDSThe hepatic lipid composition of patients with nonalcoholic steatohepatitis and nonalcoholic fatty liver has recently been comprehensively profiled by Puri et al. 12 In this study, consisting of 9 subjects in each group, total hepatic lipid content and triacylglycerol were markedly elevated compared with age, sex, and body mass index matched controls. Hepatic FFAs were unchanged across the spectrum of liver injury. Within triacylglycerol and diacylglycerol, the saturated fatty acid palmitic acid and the monounsaturated fatty a...

show abstract

“…TNF-␣ further induces de novo lipogenesis in hepatocytes, leading to lipid accumulation. In case of TNF-␣ signal-chain interruption -either pharmacologic or genetic -, reduced lipid accumulation can be documented [34,35] . Taken together, these findings indicate that TNF-␣ is one of the critical factors for occurrence and progression of NAFLD/ NASH.…”

Section: Adipokines Are Involved In the Development Of Nashmentioning

confidence: 99%