We have shown that transgenic expression of DGAT1 results in cardiac dysfunction in the absence of obesity, elevations in plasma lipid levels, or insulin resistance. These results support the hypothesis that cardiac steatosis has detrimental effects on myocyte function independent of those effects that accrue from excessive generalized adiposity or elevated plasma lipid levels.
Our results are seemingly in contrast with previous studies of DGAT1 and lipid accumulation. In studies of isolated fibroblasts from DGAT1-null mice, treatment with the fatty acid oleate resulted in increased cell death, suggesting that the inability to esterify fatty acids into neutral triglycerides efficiently potentiates the ability of the former to promote cellular dysfunction.37
In a recent study, Liu et al38
independently demonstrated that cardiac transgenic expression of DGAT1 results in triglyceride accumulation. In contrast to our findings, cardiac function in their transgenic model was unaffected. They go on to show that in a double transgenic model, in which both DGAT1 and ACS are coexpressed, DGAT1 expression appears to be cardioprotective. In this model, DGAT1 expression improves cardiac function and results in reduced diacylglycerol and ceramide content, as compared to the single ACS transgenic mouse.
These seemingly disparate results may be explained, in part, by the time course of the observed responses. The effect of DGAT1 overexpression on cardiac function in the Liu et al study was assessed in mice aged 3 to 4 months. The MHC-DGAT1 Tg mice in our study demonstrate modest but significant cardiac phenotypic changes at 12 weeks of age but required a year to develop severe cardiomyopathy. One might interpret these data, in aggregate, as suggesting that DGAT1-dependent triglyceride synthesis can be cardio-protective in the face of acute or subacute fatty acid overload. In this model, enhanced expression of DGAT1 would provide a mechanism to sequester fatty acids and blunt their toxic potential. Indeed, it has been suggested that such a mechanism occurs in the exercise-induced accumulation of triglyceride in skeletal muscle, a phenomenon termed the athlete’s paradox.23,39
However, with time and even in situations where there is little or no threat of toxicity from plasma fatty acids, the DGAT1-dependent accrual of triglycerides within myocyte vesicles would provide a chronic source of endogenous triglyceride metabolites and fatty acids that could result in cellular toxicity.
The MHC-DGAT1 Tg hearts displayed considerable interstitial fibrosis, a hallmark of advanced cardiomyopathy and heart failure in animal models40
as well as human patients.41
It has also been observed in the hearts of Zucker fatty rats42
and ob/ob mice.43
The current study suggests that this interstitial fibrosis and increased remodeling activity can result solely from cardiac steatosis in the absence of elevations in plasma lipid levels. It also implies that the changes observed in the interstitial compartment as the cardiomyopathy develops are dependent on abnormalities originating in the myocyte itself since the genetic lesion is confined to this compartment. This could represent an indirect lipotoxic effect of fatty acids that are hydrolyzed from myocyte triglycerides and released into the interstitial compartment. Alternatively, it could reflect release of autocrine/paracrine factors by the myocytes in response to lipotoxic injury that, in turn, influence neighboring cardiac fibroblasts to increase cellular proliferation and synthesis of extracellular matrix.
Lipotoxicity has been associated with mitochondrial dysfunction in other systems,44
and mitochondrial biogenesis is thought to be adversely affected in obesity and type 2 diabetes mellitus.29
Skeletal muscle biopsies in type 2 diabetes mellitus patients show reduced oxidative function and decreased mitochondrial area, findings that correlate with reduced insulin sensitivity.45,46
Both the number and function of mitochondria in the heart are linked inversely to changes in cardiac output that occur in response to physiological or pathological stress.47
We found a significant reduction in measures of mitochondrial number, expression of mitochondrial encoded genes, and key transcription factors known to be important in mitochondrial biogenesis in the MHC-DGAT1 Tg hearts. We also noted reduced expression of the transcriptional coactivator PGC1α
, a protein which has been shown to play an important role in mitochondrial biogenesis and fatty acid metabolism.48
is reduced in both heart and skeletal muscle in a rat model of congestive heart failure,49
and deletion of the PGC1α
gene in 2 independently generated mouse lines results in a cardiomyopathic phenotype.36,50
Expression of PGC1α
target genes are also reduced in myocardium of human patients with heart failure.51
Our findings raise the intriguing possibility that lipid accumulation and the lipotoxicity that it engenders might impair mitochondrial biogenesis and contribute to the development of cardiomyopathy, at least in part, through suppression of PGC1α
We have used cardiac selective expression of DGAT1, a rate-limiting terminal enzyme in triglyceride synthesis, to create a murine model of isolated cardiac steatosis. Over time, these mice demonstrate increased myocardial lipid deposition and progress to cardiomyopathy with compromised systolic and diastolic function. The protracted time course for development of cardiomyopathy in the MHC-DGAT1 Tg hearts is noteworthy in that it suggests that cardiac steatosis has insidious yet steadily progressive effects on myocyte function reminiscent of the dysfunction seen in obesity-related52
or diabetic cardiomyopathy,53
both of which have been associated with myocyte steatosis.2,54
This supports the notion that chronic accumulation of neutral lipid within myocardial cells in morbid obesity and diabetes mellitus is not a benign process and may well contribute to the cardiomyopathy and heart failure seen late in the course of those diseases.