Nonalcoholic Hepatic Steatosis in Zucker Diabetic Rats: Spontaneous Evolution and Effects of Metformin and Fenofibrate

Abstract

No specific treatment for nonalcoholic hepatic fatty liver disease has been defined. We followed the spontaneous evolution of liver steatosis and tested the therapeutic usefulness of metformin and fenofibrate in a model of steatosis, the Zucker diabetic fatty (ZDF) rat. ZDF and control rats were studied at 7, 14, and 21 weeks. After initial study at 7 weeks, ZDF rats received no treatment, metformin or fenofibrate until studies at 14 or 21 weeks. ZDF rats were obese, hypertriglyceridemic, insulin resistant at 7 weeks, type 2 diabetic at 14, diabetic with insulin deficiency at 21. They had steatosis at 7 weeks with increased hepatic expression and activity of lipogenesis. Steatosis was unchanged at 14 and 21 weeks despite lower expression and activity of lipogenesis. Metformin and fenofibrate did not modify energy intake or expenditure or the evolution of diabetes. Both compounds decreased plasma triacylglycerol (TAG) concentrations. Hepatic TAG content was reduced by fenofibrate at 14 and 21 weeks but only at 21 weeks by metformin. Metformin had no significant effects on the expression in liver of genes of fatty acids metabolism. The beneficial effect of fenofibrate occurred despite increased expression of genes involved in the uptake and activation of fatty acids. Acyl‐CoA oxidase (ACO) and carnitine palmitoyltransferase I (CPTI) mRNA levels were increased by fenofibrate showing evidence of increased lipid oxidation. To conclude, metformin had only moderate effects on liver steatosis. The effects of fenofibrate was more marked but remained mild.

Stimulation of fat accumulation in hepatocytes by PGE2-dependent repression of hepatic lipolysis, β-oxidation and VLDL-synthesis

“…35 The central role of CPT-1 in the development of hepatic steatosis has also been shown both in vivo and in vitro: moderate overexpression 36 or induction of CPT-1 has been shown to improve diet-induced steatosis of the liver in different NASH models. 37,38 By contrast, a reduction of CPT-1 activity along with other mitochondrial defects, which preceded the development of steatosis and NASH, has been implicated as leading cause for disease development in the Otsuka Long-Evans Tokushima Fatty rat model of NASH. 39 In further support of a contribution of impaired mitochondrial b-oxidation to steatosis, inhibition of CPT-1 has been identified as a possible underlying mechanism in drug-induced steatosis.…”

Changing pattern of gene expression is associated with ventricular myocyte dysfunction and altered mechanisms of Ca2+signalling in young type 2 Zucker diabetic fatty rat heart

“…Previously reported features of ZDF rats also include raised plasma haemoglobin A 1c , impaired glucose tolerance, hyperinsulinaemia, hyperlipidaemia and moderate hypertension (Welch et al 2006;Pontes Andersen et al 2008;Forcheron et al 2009). …”

Combining metformin and aerobic exercise training in the treatment of type 2 diabetes and NAFLD in OLETF rats

“…Fatty acid oxidation assays were performed in fresh hepatic tissue preparations, using radiolabeled [1-14 C]palmitate (American Radiochemicals) as described previously (42). Briefly, the oxidation rate of [ 14 C]palmitate was measured by collecting and counting the 14 CO2 produced (representing complete fatty acid oxidation) and 14 C-labeled acid-soluble metabolites (representing incomplete fatty acid oxidation) that were collected within a trapping device and counted with a liquid scintillation counter. Palmitate oxidation experiments were performed in the presence (100 uM) or absence of etomoxir (a specific inhibitor of mitochondrial carnitine palmitoyl-CoA transferease-1 and entry into the mitochondria) to examine the relative contribution of mitochondrial (Ϫ etomoxir) and extramitochondrial organelles (ϩ etomoxir) in total fatty acid oxidation, as described previously (46).…”

“…Human studies have shown that continued metformin use helps sustain reductions in circulating serum alanine aminotransferase (ALT) levels in individuals at risk for developing type 2 diabetes (22) and with early liver disease (31), and these reductions may be due in part to metformin-induced reductions in body weight (22). Metformin also has been shown to improve liver TG content in some rodent models of diabetes and NAFLD (14,25). However, it is unknown whether the efficacy of treating NAFLD in the setting of type 2 diabetes may be enhanced if metformin was taken in combination with exercise.…”