Objectives: 

Thiazolidinediones (TZD) are widely used insulin-sensitizing pharmacological agents in Type 2 Diabetes therapy. Although direct actions of TZD in adipose tissue have been widely reported, the hepatic actions of these drugs are not completely understood to date. To address this, we aim to evaluate TZD effects in hepatic lipid intermediary metabolism, namely hepatic de novo lipogenesis and triglycerides export rate.

Materials: 

To address this, adult male Wistar rats were maintained for 2-weeks either on a normal chow diet or on a normal chow diet where the drinking water was replaced by 35% (w/v) sucrose-enriched water (HS). Another group of HS-fed animals was treated with troglitazone (0.2% in the diet), a well-known TZD agent. At the night before the end of the study, rats were provided deuterated water (3% target enrichment) and maintained overnight on 3% deuterium-enriched drinking water. On the morning after, animals were given an intraperitoneal injection of poloxomer 407 (1,000 mg/kg bw) and plasma triglycerides evaluated at different intervals in order to assess hepatic triglycerides export rate. After 120-min, animals were sacrificed and liver and blood samples collected. Isolated hepatic triglycerides were quantified and together with plasma water analyzed for 2H-enrichment by 2H NMR Spectroscopy to quantify hepatic de novo lipogenesis.

Results: 

We found that the accumulation of hepatic triglycerides in sucrose-fed rats is not associated with decreased hepatic triglycerides export but rather with increased hepatic triglycerides synthesis, partly attributable to increased de novo lipogenesis. In high sucrose-fed rodents, TZD treatment completely restored hepatic triglycerides to normal chow rodent levels, through direct actions of TZD on hepatic de novo lipogenesis.

Conclusions: 

In pathophysiological animal models, TZD exert an inhibitory effect on hepatic de novo lipogenesis by mechanisms currently under investigation.