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The calcium/calmodulin-dependent protein phosphatase calcineurin stimulates cardiac hypertrophy in response to numerous stimuli. Calcineurin activity is suppressed by association with modulatory calcineurin-interacting protein (MCIP)1/DSCR1, which is up-regulated by calcineurin signaling and has been proposed to function in a negative feedback loop to modulate calcineurin activity. To investigate the involvement of MCIP1 in cardiac hypertrophy in vivo, we generated MCIP1 null mice and subjected them to a variety of stress stimuli that induce cardiac hypertrophy. In the absence of stress, [MCIP1.sup.-/-] animals exhibited no overt phenotype. However, the lack of MCIP1 exacerbated the hypertrophic response to activated calcineurin expressed from a muscle-specific transgene, consistent with a role of MCIP1 as a negative regulator of caicineurin signaling. Paradoxically, however, cardiac hypertrophy in response to pressure overload or chronic adrenergic stimulation was blunted in [MCIP1.sup.-/-] mice. These findings suggest that MCIP1 can facilitate or suppress cardiac calcineurin signaling depending on the nature of the hypertrophic stimulus. These opposing roles of MCIP have important implications for therapeutic strategies to regulate cardiac hypertrophy through modulation of calcineurin-MCIP activity.

We hypothesized that the lipid-activated transcription factor, the peroxisome proliferator-activated receptor [Alpha] (PPAR[Alpha]), plays a pivotal role in the cellular metabolic response to fasting. Short-term starvation caused hepatic steatosis, myocardial lipid accumulation, and hypoglycemia, with an inadequate ketogenic response in adult mice lacking PPAR[Alpha] (PPAR[[Alpha].sup.-/-]), a phenotype that bears remarkable similarity to that of humans with genetic defects in mitochondrial fatty acid oxidation enzymes. In PPAR[[Alpha].sup.+/+] mice, fasting induced the hepatic and cardiac expression of PPAR[Alpha] target genes encoding key mitochondrial (medium-chain acyl-CoA dehydrogenase, carnitine palmitoyltransferase I) and extramitochondrial (acyl-CoA oxidase, cytochrome P450 4A3) enzymes. In striking contrast, the hepatic and cardiac expression of most PPAR[Alpha] target genes was not induced by fasting in PPAR[[Alpha].sup.-/-] mice. These results define a critical role for PPAR[Alpha] in a transcriptional regulatory response to fasting and identify the PPAR[[Alpha].sup.-/-] mouse as a potentially useful murine model of inborn and acquired abnormalities of human fatty acid utilization.

Highlights a study that hypothesized that the lipid-activated transcription factor peroxisome proliferator-activated receptor alpha (PPAR...) play a pivotal role in the cellular metabolic response to fasting. Alteration of hepatic and cardiac lipid homeostatic response to fasting in PPAR...; How the glucose homeostatic response to fasting is altered in PPAR alpha mice; Expression of genes encoding mitochondrial fatty acid oxidation enzymes.