Divergent effects of peroxisome proliferator–activated receptor‐γ ligands in human and mouse nonalcoholic steatohepatitis†‡

Caldwell, Stephen H.; Argo, Curtis K.

doi:10.1002/hep.21881

Cited by 8 publications

(4 citation statements)

References 23 publications

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“…In ob/ob and DIO mice rosiglitazone effectively lowered blood glucose levels but increased liver steatosis 22. This phenomenon appears to be mouse‐specific and is likely due to the elevated expression of the PPAR‐γ receptor in the ob/ob mouse compared to low levels in normal human livers 23. Nevertheless, the data show that increasing insulin sensitivity does not necessarily decrease steatosis.…”

Section: Discussionmentioning

confidence: 91%

Inhibiting glycosphingolipid synthesis ameliorates hepatic steatosis in obese mice #

Zhao¹,

Przybylska²,

Wu³

et al. 2009

Hepatology

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Steatosis in the liver is a common feature of obesity and type 2 diabetes and the precursor to the development of nonalcoholic steatohepatitis (NASH), cirrhosis, and liver failure. It has been shown previously that inhibiting glycosphingolipid (GSL) synthesis increases insulin sensitivity and lowers glucose levels in diabetic rodent models. Here we demonstrate that inhibiting GSL synthesis in ob/ob mice not only improved glucose homeostasis but also markedly reduced the development of hepatic steatosis. The ob/ob mice were treated for 7 weeks with a specific inhibitor of glucosylceramide synthase, the initial enzyme involved in the synthesis of GSLs. Besides lowering glucose and hemoglobin A1c (HbA1c) levels, drug treatment also significantly reduced the liver/body weight ratio, decreased the accumulation of triglycerides, and improved several markers of liver pathology. Drug treatment reduced liver glucosylceramide (GL1) levels in the ob/ob mouse. Treatment also reduced the expression of several genes associated with hepatic steatosis, including those involved in lipogenesis, gluconeogenesis, and inflammation. In addition, inhibiting GSL synthesis in dietinduced obese mice both prevented the development of steatosis and partially reversed preexisting steatosis. Conclusion: These data indicate that inhibiting GSL synthesis ameliorates the liver pathology associated with obesity and diabetes, and may represent a novel strategy for treating fatty liver disease and NASH. (HEPATOLOGY 2009;50:85-93.)

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Section: Discussionmentioning

confidence: 91%

Inhibiting glycosphingolipid synthesis ameliorates hepatic steatosis in obese mice #

Zhao¹,

Przybylska²,

Wu³

et al. 2009

Hepatology

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“…The incidence of NAFLD is rapidly increasing worldwide because of the obesity and type 2 diabetes epidemics [4,5]. The prevailing hypothesis for the pathogenesis of NAFLD is inflammation and fibrosis caused by chronic fatty infiltration in the liver [6].…”

mentioning

confidence: 99%

High serum vitamin D levels reduce the risk for nonalcoholic fatty liver disease in healthy men independent of metabolic syndrome

et al. 2013

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“…These changes were also associated with increase in hepatic oxidative stress [21]. The cause of these divergent effects of rosiglitazone is not fully understood [22].…”

mentioning

confidence: 99%

Hepatic Effects of Rosiglitazone in Rats with the Metabolic Syndrome

Ackerman

Oron‐Herman

Pappo

et al. 2010

Basic Clin Pharma Tox

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Rats given fructose-enriched diet develop many characteristics of the human metabolic syndrome and non-alcoholic fatty liver disease. In this study, we characterized the hepatic effects of rosiglitazone in fructose-enriched diet rats. Rats were randomly divided into three groups. One group was maintained on standard rat chow diet for 6 weeks, whereas the other two groups were given fructose-enriched diet for 6 weeks. Four weeks after the initiation of fructose-enriched diet, one of the fructose-enriched diet groups was also given rosiglitazone (10 mg ⁄ kg ⁄ day) for an additional 2 weeks. Rosiglitazone administration to the fructose-enriched diet rats was associated with decreases in the following parameters: blood pressure ()17%), plasma triglycerides ()62%), hepatic total lipids ()19%), hepatic triglycerides ()61%), hepatic malondialdehyde ()88%), glutathione reductase activity ()84%). An increase in adiponectin plasma levels (+329%), hepatic phospholipids (+46%), hepatic a-tocopherol concentrations (+24%) and hepatic paraoxonase activity (+68%) was observed. Rosiglitazone caused a decrease in hepatic macrovesicular steatosis score but no change in hepatic fibrosis. Administration of rosiglitazone, to rats with the metabolic syndrome has limited hepatic favourable effects: it improves hepatic lipid metabolism, decreases macrovesicular steatosis and improves some of the hepatic oxidative-anti-oxidative milieu but has no effect on hepatic fibrosis.Non-alcoholic fatty liver disease and non-alcoholic steatohepatitis are increasingly recognized causes of liver diseases and liver-related mortality [1,2].The best known risk factor for non-alcoholic fatty liver disease is the presence of the metabolic syndrome that includes insulin resistance, diabetes mellitus type 2, visceral (central) obesity, overall obesity, hyperlipidaemia (mainly hypertriglyceridaemia) and hypertension [1,2]. Insulin resistance is thought to be the core of the metabolic syndrome and connects all its components [2,3]. Recent evidence suggests that the severity of hepatic histology in non-alcoholic fatty liver disease patients is closely associated with markers of metabolic syndrome [4]. Administration of thiazolidinedione drugs like rosiglitazone, which are a family of peroxisome proliferator-activated receptor gamma (PPARc) agonists, reduces plasma glucose levels, improves pancreatic islet b-cell function, improves insulin sensitivity and increases adiponectin plasma level [5]. Rosiglitazone may be used for the treatment of type 2 diabetes mellitus [5]. It increases insulin sensitivity in diabetic subjects but also in patients with non-alcoholic steatohepatitis, irrespective of whether they were normo or hyperglycaemic [6,7]. Moreover, administration of rosiglitazone or pioglitazone, another thiazolidinedione, to human subjects and certain strains of rats with non-alcoholic steatohepatitis was reported to cause significant improvement in hepatic histology especially reduction of hepatic steatosis. Only few of the studies reported regr...

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Divergent effects of peroxisome proliferator–activated receptor‐γ ligands in human and mouse nonalcoholic steatohepatitis†‡

Cited by 8 publications

References 23 publications

Inhibiting glycosphingolipid synthesis ameliorates hepatic steatosis in obese mice #

Inhibiting glycosphingolipid synthesis ameliorates hepatic steatosis in obese mice #

High serum vitamin D levels reduce the risk for nonalcoholic fatty liver disease in healthy men independent of metabolic syndrome

Hepatic Effects of Rosiglitazone in Rats with the Metabolic Syndrome

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