Apolipoprotein B Secretion Is Regulated by Hepatic Triglyceride, and Not Insulin, in a Model of Increased Hepatic Insulin Signaling

Objective-States of insulin resistance, hyperinsulinemia, and hepatic steatosis are associated with increased secretion of triglycerides (TG) and apolipoprotein B (apoB), even though insulin targets apoB for degradation. We used hepatic-specific phosphatase and tensin homologue deleted on chromosome 10 (Pten) knockout (hPten-ko) mice, with increased hepatic insulin signaling, to determine the relative roles of insulin signaling and hepatic TG in regulating apoB secretion. Methods and Results-TG and apoB secretion was elevated in hPten-ko mice. When hepatic TG was reduced by inhibition of diacylglycerol acyltransferase 1/diacylglycerol acyltransferase 2 or sterol regulatory element-binding protein-1c, both TG secretion and apoB secretion fell without changes in hepatic insulin signaling. Acute reconstitution of hPten reduced hepatic TG content, and both TG and apoB secretion fell within 4 days despite decreased hepatic insulin signaling. Acute depletion of hepatic Pten by adenoviral introduction of Cre into Pten floxed mice caused steatosis within 4 days, and secretion of both TG and apoB increased despite increased hepatic insulin signaling. Even when steatosis after acute Pten depletion was prevented by pretreatment with SREBP-1c antisense oligonucleotides, apoB secretion was not reduced after 4 days. Ex vivo results were in primary hepatocytes were similar. Conclusion-Either hepatic TG is the dominant regulator of apoB secretion or any inhibitory effects of hepatic insulin signaling on apoB secretion is very short-lived. (Arterioscler Thromb Vasc Biol. 2012;32:236-246.)