*4.2. ABCA1 and Insulin Sensitivity*

Although global *Abca1*−*/*<sup>−</sup> KO mice did not show alterations in insulin sensitivity, multiple lines of evidence suggest that ABCA1 is involved in this trait. The interaction of HDL particles and ApoA-I results in the phosphorylation and activation of AMP-activated protein kinase (AMPK), a key metabolic enzyme that increases glucose uptake in murine endothelial cells, monocytes and skeletal muscle cells [115,116]. Similarly, in primary skeletal muscle cell cultures from T2D patients, HDL/ApoA-I bound to muscle cell surface receptors (including ABCA1), inducing intracellular Ca2+ mobilization, AMPK activation and glucose uptake. Antibody-mediated ABCA1 blockade inhibited HDL/ApoA-I glucose uptake and Ca2+ release in vitro, suggesting that HDL/ApoA-I modulates skeletal muscle glucose uptake in an ABCA1-dependent manner [117]. More recently, lipid-free ApoA-I was found to increase insulin-dependent and insulin-independent glucose uptake in primary human skeletal muscle cells, which were regulated by both ABCA1 and SR-B1, and this regulation seemed to be independent of ApoA-I acting as an acceptor of cellular cholesterol [118].

Moreover, observations in adipocyte-specific *Abca1*-ad/-ad KO mice suggest a critical role for adipocyte intracellular cholesterol and ABCA1 in whole-body glucose homeostasis. These mice showed impaired glucose tolerance and lower muscle insulin sensitivity, along with significant changes in the adipose tissue expression of genes involved in cholesterol and glucose homeostasis, including *ldlr*, *abcg1*, *glut-4*, visfatin, adiponectin, and leptin. They also showed lower glucose-stimulated insulin secretion from β-cells ex vivo. Notably, reduced muscle-tissue insulin sensitivity and glucose tolerance were observed in *Abca1* deficient mice fed a high fat, high cholesterol diet, suggesting that adipocyte ABCA1 is crucial for proper adipose tissue function in response to dietary fat and cholesterol [119]. Moreover, hepatocyte-specific *Abca1* KO mice (HSKO) produced a form of selective insulin resistance, suppressing lipogenesis but with normal glucose metabolism [120]. HSKO mice had reduced hepatic insulin-stimulated Akt phosphorylation, decreased SREBP-1c activation and reduced expression of lipogenic genes, but normal glucose and insulin tolerance.
