Several mechanisms for PI-induced dyslipidemia have been proposed. They include but are not limited to decreases in hepatic and lipoprotein lipase (LPL) activity (Purnell et al. 2000
), fractional catabolic rate of VLDL-triglyceride (Shahmanesh et al. 2005
), or fat clearance owing to impaired LPL-mediated clearance of triglyceride-rich lipoproteins (Sekhar et al. 2005
PIs also have a direct effect on lipoprotein production under the regulation of the sterol regulatory element–binding proteins (SREBPs) (Riddle et al. 2001
), which function as intracellular lipid sensors (Horton et al. 2002
). SREBPs are activated when intracellular lipid levels drop; they are then transported from the ER to the nucleus, where they up-regulate the expression of genes involved in cholesterol synthesis, transport, and triglyceride and fatty acid biogenesis. In the nucleus, the SREBPs are degraded by the proteasomes (Hirano et al. 2001
). Several PIs, including IDV and RTV, have been shown to activate SREBP-1 and SREBP-2 (Riddle et al. 2001
; Williams et al. 2004
) in hepatocytes. Some PIs may also affect SREBP translocation into the nucleus facilitated by lamins A and C and resulting in SREBP-1 mislocalization (Caron et al. 2001
; Caron et al. 2003
; Coffinier et al. 2007
A consequence of SREBP activation is an excessive accumulation of intracellular cholesterol in the ER membranes, which is detrimental for maintaining intracellular homeostasis and can trigger an intracellular mechanism for sensing stress, regulating cell growth, differentiation, and apoptosis that is known as the unfolded protein response (UPR) (Xu et al. 2005
; Zhang and Kaufman 2004
). The concentration of misfolded or unfolded proteins in the ER increases and triggers cellular signaling pathways to restore homeostasis. This process involves translational attenuation, up-regulation of ER chaperones, and degradation of unfolded proteins. Although these pathways are aimed at restoring homeostasis, in the extreme, they ultimately result in apoptosis.
Proteasome inhibition and the resultant activation of UPR would therefore seem to be a common link between the effects of PIs in adipocytes and hepatocytes, cells with an important role in the metabolic effects of these drugs. However, the acute effects of the PIs are strikingly different in adipocytes and hepatocytes. PIs inhibit triglyceride synthesis and glucose transport in adipocytes; conversely, they increase triglyceride biosynthesis in hepatocytes without affecting glucose uptake. Lipogenic gene expression is also differentially altered (Parker et al. 2005
). In hepatocytes, less than 1% of profiled RNA sequences were increased or decreased by more than two-fold, and nearly four times as many genes were induced than repressed. A detailed analysis revealed induction of multiple genes involved in lipid metabolism and gluconeogenesis. Similar in vivo effects on hepatic lipogenic gene expression following RTV treatment in the rat have been reported (Lum et al. 2007
). The opposite effect was observed in adipocytes, with more genes repressed than induced. Key lipogenic transcription factors (PPAR-β and SREBP-1c) and multiple enzymes involved in lipid biosynthesis were down-regulated in the adipocyte. Differences between the effects of PIs were apparent in both adipocytes and hepatocytes, with some PIs such as ATV having the least impact in both cell types (Parker et al. 2005
The contrasting effect on lipid synthesis in the two cell types is particularly important. In adipocytes, suppression of glucose uptake, and thereby energy storage, is associated with diminished lipid synthesis (). Inhibition of the proteasome in hepatocytes extends the longevity of the key SREBPs involved in regulating lipid synthesis (). Thus, at the cellular level, these results suggest a metabolic shift in the fat energy storage from the adipocyte to the hepatocyte, and possibly other nonadipose tissues.
Figure 4 Protease inhibitors stimulate hepatic lipid synthesis by maintaining the nuclear activity of the SREBP regulatory transcription factors. GLUT2 is the major hepatocyte glucose transporter, but unlike GLUT4 in the adipocyte, GLUT2 appears to be unaffected (more ...)
It is interesting to note that intracellular events mirror the clinical manifestations of fat redistribution where lipoatrophy, in the form of depleted adipocyte triglyceride stores, is frequently observed at the same time as hyperlipidemia and increased hepatic lipid secretion. Taken together, these observations suggest that both proteasome inhibition and activation of UPR by stress signals such as chronic HIV infection or by drugs such as PIs can independently affect the normal regulation of cellular fuel sensing and storage. Long-term disturbance in cellular fuel sensing may underlie the pathophysiology of fat redistribution.