Abstract
Expression of apoE in adipocytes has been shown to have an important role in modulating adipocyte triglyceride (TG) metabolism and gene expression that is independent of circulating and extracellular apoE. The impact of adipocyte expression of common human apoE isoforms was evaluated using adipocytes harvested from human apoE2, -3, and -4 knock-in mice. Expression of the apoE2 isoform was associated with an increase in adipocyte apoE gene expression and apoE synthesis. Newly synthesized apoE2 was unstable in adipocytes and demonstrated increased degradation and decreased secretion. ApoE2-expressing mice were hyperlipidemic, and had increased size of gonadal fat pads and of adipocytes, compared with apoE3 mice. In isolated cells, however, expression of the apoE2 isoform produced defective lipogenesis and increased TG hydrolysis. Incubation of adipose tissue with apoE3-containing TG-rich lipoproteins resulted in a significant increase in TG in adipose tissue from apoE3 and -E4 mice, but not apoE2 mice. Reduced capacity to internalize FFA as lipogenic substrate contributed to defective lipogenesis. Newly synthesized apoE2 is unstable in adipocytes and results in decreased adipocyte TG synthesis and defective FA uptake. These changes recapitulate those observed in apoE knockout adipocytes and have implications for understanding metabolic disturbances in humans expressing the E2 isoform.
Highlights
Expression of apoE in adipocytes has been shown to have an important role in modulating adipocyte triglyceride (TG) metabolism and gene expression that is independent of circulating and extracellular apoE
An important role has been established for endogenous adipocyte apoE expression, separate from circulating and extracellular apoE, for regulating adipocyte substrate metabolism [4,5,6,7]
In the current set of studies, we establish that the expression of the apoE2 isoform under the control of its endogenous gene control elements has a significant impact on adipocyte apoE synthesis and degradation
Summary
Expression of apoE in adipocytes has been shown to have an important role in modulating adipocyte triglyceride (TG) metabolism and gene expression that is independent of circulating and extracellular apoE. Synthesized apoE2 is unstable in adipocytes and results in decreased adipocyte TG synthesis and defective FA uptake These changes recapitulate those observed in apoE knockout adipocytes and have implications for understanding metabolic disturbances in humans expressing the E2 isoform.—Huang, Z. Adipocytes that do not express endogenous apoE are smaller, contain less lipid, display a defect in lipogenesis and substrate acquisition from extracellular lipoproteins, and have alterations in the expression of genes controlling adipocyte lipid turnover [4,5,6,7]. These defects cannot be corrected by the provision of extracellular apoE in vitro or in vivo, but can be corrected by adenoviral-mediated expression of endogenous apoE in adipocytes [4, 5] Because of these effects on adipose tissue metabolism, endogenous adipocyte apoE importantly influences the systemic distribution of substrate in intact animals [5]. Adipose tissue dysfunction has been associated with the systemic expression of apoE4 in mice maintained on a high-fat Western diet [27, 28]
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