Compensatory Increase in Hepatic Lipogenesis in Mice with Conditional Intestine-specific Mttp Deficiency

Abstract

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 tamoxifeninducible, 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 ϳ80% 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. The mobilization and secretion of triglyceride (TG)3 -rich lipoproteins from mammalian enterocytes and hepatocytes are critically dependent on the integrated function of at least two dominant genes. These include the microsomal triglyceride transfer protein (MTTP), a resident endoplasmic reticulum protein that facilitates the transfer of neutral lipid to a large hydrophobic acceptor protein, apolipoprotein B (apoB) (1). ApoB in turn functions as a requisite structural component of the surface of TG-rich lipoproteins and plays a vital role in plasma lipoprotein metabolism (2). Their physiological importance is exemplified through the phenotypes associated with abetalipoproteinemia and homozygous familial hypobetalipoproteinemia, where structural defects in either the MTTP or APOB gene, respectively, lead to a syndrome of hypocholesterolemia (including low levels of high density lipoprotein (HDL)), mild fat malabsorption with fasting lipid accumulation in the small intestine along with hepatic steatosis (3, 4).Exploration of the mechanisms underlying these phenotypes has been advanced through studies in murine genetic models in which either the Apob or Mttp gene was deleted. Germ line deletion of either the Apob or Mttp gene, however, resulted in embryonic lethality (5-7), the result of defective lipid delivery to the developing embryo, necessitating alternative approaches to the s...

Lipid Absorption Defects in Intestine-specific Microsomal Triglyceride Transfer Protein and ATP-binding Cassette Transporter A1-deficient Mice

“…However, although FFA accumulation has not been observed in the liver-specific MTP knock-out mice (6, 36), intestine-specific MTP ablation has been reported to increase cellular free fatty acids (7). We also observed an ϳ1.5-fold increase in intestinal free fatty acids (Table 1).…”

“…However, Xie et al (7) reported that I-Mttp Ϫ/Ϫ decreased fractional cholesterol absorption by ϳ60 -70%. This discrepancy is the result of two different methods used to measure cholesterol absorption.…”

“…Compensatory Changes in Hepatic Lipid Metabolism in Intestine-specific MTP and ABCA1 Knock-out Mice-Xie et al (7) reported increased hepatic lipogenesis in intestine-specific MTP-deficient mice. Consistent with these studies, we observed significant increases in mRNA levels of SREBP-1c, fatty-acid synthase (FAS), and acetyl-CoA carboxylase (ACC), but stearoylCoA desaturase-1 (SCD1) levels were unaltered (Fig.…”

“…However, their combined deficiency results in 60% reduction, suggesting that the transport of free and esterified cholesterol occurs by two different additive mechanisms that contribute to efficient cholesterol absorption. A recent study showed that ϳ30% of cholesterol is absorbed via the HDL pathway in the absence of MTP (7). Thus, there is significant evidence to suggest that these two pathways contribute to cholesterol absorption.…”

Chronic high-fat diet affects intestinal fat absorption and postprandial triglyceride levels in the mouse

“…This protein plays a crucial role in chylomicron synthesis. Indeed, an intestine-specific MTP gene invalidation produces a dramatic decrease in chylomicron synthesis and secretion (5). Finally, the induction of apoA-IV expression found in lipid-fed mice might also facilitate intestinal lipoprotein production (27).…”