Microsomal TG transfer protein (
MTTP) is required for the assembly and secretion of TG (TG)-rich
lipoproteins from both enterocytes and hepatocytes. Liver-specific deletion of
Mttp produced a dramatic reduction in plasma
very low density lipoprotein-TG and virtually eliminated
apolipoprotein B100 (apoB100) secretion yet caused only modest reductions in plasma
apoB48 and
apoB48 secretion from primary hepatocytes. These observations prompted us to examine the phenotype following intestine-specific
Mttp deletion because murine, like human enterocytes, secrete virtually exclusively
apoB48. We generated mice with conditional
Mttp deletion in villus enterocytes (
Mttp-IKO), using a
tamoxifen-inducible, intestine-specific Cre transgene. Villus enterocytes from chow-fed
Mttp-IKO mice contained large cytoplasmic TG droplets and no
chylomicron-sized particles within the secretory pathway. Chow-fed,
Mttp-IKO mice manifested
steatorrhea, growth arrest, and decreased
cholesterol absorption, features that collectively recapitulate the phenotype associated with
abetalipoproteinemia.
Chylomicron secretion was reduced dramatically in vivo, in conjunction with an approximately 80% decrease in
apoB48 secretion from primary enterocytes. Additionally, although plasma and hepatic
cholesterol and TG content were decreased,
Mttp-IKO mice demonstrated a paradoxical increase in both hepatic lipogenesis and
very low density lipoprotein secretion. These findings establish distinctive features for
MTTP involvement in intestinal
chylomicron assembly and secretion and suggest that hepatic lipogenesis undergoes compensatory induction in the face of defective intestinal TG secretion.