Sterol regulatory element binding proteins SREBPs
Sterol regulatory element binding proteins (SREBPs) regulate transcription of genes involved in fatty Amrubicin receptor synthesis  (fatty acid synthase, and acetyl-CoA carboxylase) as well as triglyceride synthesis . SREBP-1 protein levels are reduced in 3T3-F442A adipocytes  and increased in primary rat hepatocytes  exposed to the HIV-PI indinavir. Interestingly, ritonavir administration to mice increased SREBP-1 protein expression in liver and adipose tissue . Indinavir administration to ZDF fa/fa rats increased SREBP-1 protein levels in skeletal muscle, liver, and adipose tissue, and this was associated with induction of the suppressor of cytokine signaling-1 (SOCS-1) cascade . Also, SREBP-1 protein levels were increased in L6 myotubes exposed to ritonavir, ATV, and LPV alone or ATV/r, and LPV/r in combination. Together, these findings indicate that indinavir, ritonavir, and ATV/r, LPV/r, and DRV/r increase SREBP-1 protein levels in skeletal muscle cells from several mammalian species.
There were some limitations to this in vitro study. Several factors, in addition to HIV-PI, contribute to dysregulated fatty acid and lipid metabolism in HIV-infected people. We cannot account for all these factors (e.g., genetics, physical activity, diet, HIV replication, host response to HIV-infection, and other HAART components) in our model system. The primary goal was to isolate the effects of select HIV-PIs that are commonly used on palmitate metabolism. Also, myotubes were acutely exposed to HIV-PIs, and more chronic exposures should be examined to evaluate the durability/sustainability of these acute effects on myotube fatty acid metabolism.
Introduction Aging entails adaptations in energy metabolism to maintain cardiac pump function (Kates et al., 2003, McMillin et al., 1993). For example, fatty acid oxidation, which is typically the primary oxidizable substrate for myocardial bioenergetics, declines with age in rodents (Abu-Erreish et al., 1977, Hyyti et al., 2010, McMillin et al., 1993) and also in humans (Kates et al., 2003). While glucose oxidation appears to compensate this loss (Kates et al., 2003, McMillin et al., 1993), there is increasing evidence that such a shift in metabolism comes at a price, primarily in lower bioenergetic reserve capacity that limits response to heightened energy demands (Davila-Roman et al., 2002, Koonen et al., 2007, van der Meer et al., 2008). Moreover, as myocytes have limited means for exporting fatty acids in the form of triacylglyceride (Lewin and Coleman, 2003), lower fatty acid oxidation may shunt lipids into non-oxidizing metabolic pathways and/or lipid storage in the myocardium (Koonen et al., 2007, Sharma et al., 2004, van der Meer et al., 2008). In its extreme, the age-associated decline in fatty acid-driven mitochondrial bioenergetics may thus initiate a form of myocardial lipotoxicity (Brindley et al., 2010, Slawik and Vidal-Puig, 2006, Wende and Abel, 2010). Therefore, it is important to understand the mechanism for lower fatty acid oxidation in the aging heart muscle. While age-associated alterations in cardiac energy metabolism are undoubtedly multifactorial, several reports implicate carnitine palmitoyltransferase 1 (CPT1) as a key enzyme in the shift away from fatty acid oxidation (Lee et al., 2002, McMillin et al., 1993, Odiet et al., 1995). CPT1, the rate-controlling enzyme for overall fatty acid β-oxidation, catalyzes the condensation of acyl-CoA with l-carnitine to form acyl-carnitine esters, which are subsequently transported into mitochondria for further catabolism (Bartlett and Eaton, 2004, McGarry and Brown, 1997, Ramsay et al., 2001). There is a consensus that CPT1 activity declines with age in heart and skeletal muscle (Hansford and Castro, 1982, Kim et al., 2009, McMillin et al., 1993, Odiet et al., 1995). Moreover, down-regulation of CPT1 activity correlates with lipid accumulation and insulin resistance in rat skeletal muscle (Dobbins et al., 2001, Kim et al., 2009). Therefore, a plausible hypothesis is that lower CPT1activity is an underlying factor in the decline in fatty acid-supported myocardial bioenergetics.