Mfge8 regulates enterocyte lipid storage by promoting enterocyte triglyceride hydrolase activity
Amin Khalifeh-Soltani, Deepti Gupta, Arnold Ha, Jahangir Iqbal, Mahmood Hussain, Michael J. Podolsky, Kamran Atabai
Amin Khalifeh-Soltani, Deepti Gupta, Arnold Ha, Jahangir Iqbal, Mahmood Hussain, Michael J. Podolsky, Kamran Atabai
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Research Article Cell biology Metabolism

Mfge8 regulates enterocyte lipid storage by promoting enterocyte triglyceride hydrolase activity

Abstract

The small intestine has an underappreciated role as a lipid storage organ. Under conditions of high dietary fat intake, enterocytes can minimize the extent of postprandial lipemia by storing newly absorbed dietary fat in cytoplasmic lipid droplets. Lipid droplets can be subsequently mobilized for the production of chylomicrons. The mechanisms that regulate this process are poorly understood. We report here that the milk protein Mfge8 regulates hydrolysis of cytoplasmic lipid droplets in enterocytes after interacting with the αvβ3 and αvβ5 integrins. Mice deficient in Mfge8 or the αvβ3 and αvβ5 integrins accumulate excess cytoplasmic lipid droplets after a fat challenge. Mechanistically, interruption of the Mfge8-integrin axis leads to impaired enterocyte intracellular triglyceride hydrolase activity in vitro and in vivo. Furthermore, Mfge8 increases triglyceride hydrolase activity through a PI3 kinase/mTORC2–dependent signaling pathway. These data identify a key role for Mfge8 and the αvβ3 and αvβ5 integrins in regulating enterocyte lipid processing.

Authors

Amin Khalifeh-Soltani, Deepti Gupta, Arnold Ha, Jahangir Iqbal, Mahmood Hussain, Michael J. Podolsky, Kamran Atabai

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Figure 4

Impaired triglyceride (TG) hydrolase activity in enterocytes from Mfge8–/– and αvβ3/αvβ5–/– mice.

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Impaired triglyceride (TG) hydrolase activity in enterocytes from Mfge8–...
(A) TG hydrolase activity in the proximal jejunal segments of mice measured 2 hours after olive oil gavage. n = 5–6. (B) Effect of rMfge8 (10 μg/ml), RGE (an rMfge8 mutant that does not bind integrin, 10 μg/ml), and integrin-blocking (αv, β3, β5, and β1; 5 μg/ml) antibodies on TG hydrolase activity in the Caco-2 cell line. n = 4–6. (C) Effect of rMfge8 (10 μg/ml) in the absence and presence of integrin-blocking (αv, β3, β5, and β1; 5 μg/ml) antibodies on TG hydrolase activity in the proximal jejunal enterocytes of mice. n = 5–7. (D) Effect of rMfge8 (10 μg/ml) on TG hydrolase activity in the primary enterocytes from αvβ3/αvβ5–/– mice. n = 3. (E) TG hydrolase activity in Caco-2 cells treated with wortmannin (100 ng/ml) and rMfge8. n = 4–6. (F) Western blot of differentiated Caco-2 cells after incubation with siRNA targeting RICTOR or control siRNA. (G) TG hydrolase activity in differentiated Caco-2 cells treated with siRNA targeting RICTOR or control siRNA and rMfge8. n = 4–6. Female mice were used for panel A. Both female and male mice were used in panel C. **P < 0.01, ***P < 0.001. Paired data were analyzed by Student’s t test and group data were analyzed by 1-way ANOVA followed by a post-hoc Bonferroni test for multiple comparisons and expressed as the mean ± SEM. Ctrl., control; No Tx, no treatment.