Insulin Concentration Modulates Hepatic Lipid Accumulation in Mice in Part via Transcriptional Regulation of Fatty Acid Transport Proteins

Fatty liver disease (FLD) is commonly associated with insulin resistance and obesity, but interestingly it is also observed at low insulin states, such as prolonged fasting. Thus, we asked whether insulin is an independent modulator of hepatic lipid accumulation.In mice we induced, hypo- and hyperinsulinemia associated FLD by diet induced obesity and streptozotocin treatment, respectively. The mechanism of free fatty acid induced steatosis was studied in cell culture with mouse liver cells under different insulin concentrations, pharmacological phosphoinositol-3-kinase (PI3K) inhibition and siRNA targeted gene knock-down. We found with in vivo and in vitro models that lipid storage is increased, as expected, in both hypo- and hyperinsulinemic states, and that it is mediated by signaling through either insulin receptor substrate (IRS) 1 or 2. As previously reported, IRS-1 was up-regulated at high insulin concentrations, while IRS-2 was increased at low levels of insulin concentration. Relative increase in either of these insulin substrates, was associated with an increase in liver-specific fatty acid transport proteins (FATP) 2&5, and increased lipid storage. Furthermore, utilizing pharmacological PI3K inhibition we found that the IRS-PI3K pathway was necessary for lipogenesis, while FATP responses were mediated via IRS signaling. Data from additional siRNA experiments showed that knock-down of IRSs impacted FATP levels.States of perturbed insulin signaling (low-insulin or high-insulin) both lead to increased hepatic lipid storage via FATP and IRS signaling. These novel findings offer a common mechanism of FLD pathogenesis in states of both inadequate (prolonged fasting) and ineffective (obesity) insulin signaling

Regulation of net hepatic glucose uptake: interaction of neural and pancreatic mechanisms

International audienc

Regulation of net hepatic glucose uptake: interaction of neural and pancreatic mechanisms

International audienc

Hepatic and gut clearance of catecholamines in the conscious dog.

Our aim was to assess hepatic and gut catecholamine clearance under normal and simulated stress conditions. Following a 90-minute saline infusion period, epinephrine ([EPI] 180 ng/kg x min) and norepinephrine ([NE] 500 ng/kg x min) were infused peripherally for 90 minutes into five 18-hour fasted, conscious dogs undergoing a pancreatic clamp (somatostatin plus basal insulin and glucagon). Arterial plasma levels of EPI and NE increased from 44 +/- 9 to 2,961 +/- 445 and 96 +/- 6 to 6,467 +/- 571 pg/mL, respectively (both P < .05). Portal vein plasma levels of EPI and NE increased from 23 +/- 8 to 1,311 +/- 173 and 79 +/- 10 to 3,477 +/- 380 pg/mL, respectively (both P < .05). Hepatic vein plasma levels of EPI and NE increased from 5 +/- 2 to 117 +/- 33 and 48 +/- 10 to 448 +/- 59 pg/mL, respectively (both P < .05). Net hepatic and gut EPI uptake increased from 0.5 +/- 0.1 to 30.0 +/- 3.0 and 0.4 +/- 0.1 to 26.3 +/- 4.0 ng/kg x min, respectively (both P < .05). Net hepatic and gut NE uptake increased from 1.5 +/- 0.4 to 74.7 +/- 8.4 and 0.8 +/- 0.2 to 57.9 +/- 7.6 ng/kg x min, respectively (both P < .05). Neither the net hepatic (0.86 +/- 0.05 to 0.93 +/- 0.02) nor gut (0.45 +/- 0.10 to 0.55 +/- 0.04) fractional extraction of EPI changed significantly during the simulated stress condition. Net hepatic and gut spillover of NE increased from 0.8 +/- 0.2 to 3.5 +/- 1.3 and 0.6 +/- 0.2 to 8.8 +/- 2.0 ng/kg x min, respectively, during catecholamine infusion (both P < .05). These results indicate that (1) approximately 30% of circulating catecholamines are cleared by the splanchnic bed (16% and 14% by the liver and gut, respectively); (2) the liver and gut remove a large proportion (approximately 86% to 93% and 45% to 55%, respectively) of the catecholamines delivered to them on first pass; and (3) high levels of plasma catecholamines increase NE spillover from both the liver and gut, suggesting that the percentage of NE released from the presynaptic neuron that escapes the synaptic cleft is increased in the presence of high circulating catecholamine levels