Both Lepob/ob/Pnpla3−/−

Both Lepob/ob/Pnpla3−/− Everolimus order mice and Lepob/ob/Pnpla3+/+ littermates displayed fatty liver, and there was no difference in the hepatic TG content between the two genotypes (Table 1). Moreover, their serum ALT and AST levels were also not different (Table 1). These data indicate that loss of Pnpla3 in mice has no impact on fatty liver development under basal conditions, after they are on different fatty liver–inducing diets, or bred into a genetic model associated with

obesity and fatty liver. Lack of PNPLA3 has been postulated to perturb glucose homeostasis and insulin sensitivity in vivo.13, 21 As such, we measured the rate of glucose disposal and insulin sensitivity in wild-type and Pnpla3−/− mice by GTT and ITT. After administration of an exogenous glucose load, Pnpla3−/− mice and their wild-type littermates showed similar basal and stimulated blood glucose and insulin levels, indicating a normal glucose disposal rate and insulin secretory response to hyperglycemia in the

absence of Pnpla3 (Fig. 3A,B). Pnpla3−/− mice and wild-type littermates on a normal chow diet also displayed a similar blood glucose during ITT (Fig. 3C), indicating no significant insulin resistance associated with loss of Pnpla3. We fed these mice an HFD for 15 weeks, find more and found that the blood glucose levels during the GTT in HFD-fed Pnpla3−/− mice was minimally lower than those in wild-type littermates (Fig. 3D). The plasma insulin was, however, similar during the GTT (Fig. 3E), as was the blood glucose response during an ITT (Fig. 3F) in the two HFD-fed groups. Further examination of a cohort fed an HSD for 12 weeks also revealed no difference in either blood glucose or insulin levels during GTT (Supporting Fig. 2A,B), or blood glucose levels during an ITT (Supporting Fig. 2C), between Pnpla3−/− mice and Pnpla3+/+ mice. Finally, we examined the role of Pnpla3 in mice with the genetic obese Lepob/ob background and found that Lepob/ob/Pnpla3−/− MCE and Lepob/ob/Pnpla3+/+ mice displayed similar blood glucose and insulin levels

during GTT (Supporting Fig. 2D,E) and similar blood glucose levels during ITT (Supporting Fig. 2F). Therefore, not only did the absence of Pnpla3 not affect hepatic TG content, it also did not impact the glucose intolerance and insulin resistance that often accompany hepatic steatosis. Thus far, our data indicate that there was no evident change in hepatic TG content or whole-body glucose homeostasis between Pnpla3−/− and Pnpla3+/+ mice under four dietary conditions (CHD, HFD, HSD, and MCD) and two genotypes (C57BL/6J Lepob/ob and C57BL/6J Lep+/+). Because the PNPLA gene family encompasses three paralogous gene products in mice, we next examined the dynamics of the three paralogs in the liver under various dietary conditions. We found that the hepatic Pnpla3 mRNA in wild-type mice was markedly up-regulated (∼32-fold) by HSD feeding but only moderately by HFD (∼5-fold) (Fig. 4A, left panel).

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