Intestinal cholesterol absorption is an important contributor to systemic cholesterol homeostasis. Niemann-Pick C1 Like 1 (NPC1L1), the target of the drug ezetimibe (EZ), assists in the initial step of dietary cholesterol uptake. However, how cholesterol moves downstream of NPC1L1 is unknown. Here we show that Aster-B and Aster-C are critical for non-vesicular cholesterol movement in enterocytes, bridging NPC1L1 at the plasma membrane (PM) and ACAT2 in the endoplasmic reticulum (ER). Loss of NPC1L1 diminishes accessible PM cholesterol in enterocytes and abolishes Aster recruitment to the intestinal brush border. Enterocytes lacking Asters accumulate cholesterol at the PM and display evidence of ER cholesterol depletion, including decreased cholesterol ester stores and activation of the SREBP-2 transcriptional pathway. Aster-deficient mice have impaired cholesterol absorption and are protected against diet-induced hypercholesterolemia. Finally, we show that the Aster pathway can be targeted with a small molecule inhibitor to manipulate dietary cholesterol uptake. These findings identify the Aster pathway as a physiologically important and pharmacologically tractable node in dietary lipid absorption.
Immunophenotyping of peripheral blood mononuclear cells has been shown to be a useful, non-invasive method of predicting acute cellular rejection (ACR) following intestinal transplantation (ITx). Our objectives were to characterize differences in the T cell immunophenotype of ITx recipients in peripheral blood samples (1) collected late versus early after ITx and (1) associated with episodes of ACR and infectious enteritis. An IRB-approved, cross-sectional study of ITx recipients was performed. Peripheral blood samples were collected during normal visits and episodes of allograft dysfunction. A total of 38 patients were included in the analysis: 31 ITx recipients (87% liver-inclusive allografts) and 7 intestinal failure control patients. Of the ITx patients, 26 patients were pediatric patients (<21 years). A total of 70 samples were analyzed from ITx recipients, including 51 during normal visits and 19 during episodes of allograft dysfunction (median of 2 samples per patient; range of 1-6 samples per patient). In the late (n = 32) versus early post-ITx (n = 19) normal samples, there was a significantly higher percentage of central memory CD4 T cells (p = .001). In the ACR (n = 5) versus infectious enteritis (n = 14) samples, there was a higher percentage of CD8 T cells expressing HLA-DR (p = .002), CD57 (p < .001), and KLRG1 (p < .001) and a higher percentage of CD4 T cells expressing CD57 (p = .03). Additional studies are needed with larger cohorts to validate these changes in the T cell immunophenotype. Further elucidating T cell immunophenotypes in ITx will lead to a better understanding of immune mechanisms of allograft dysfunction, identification of potential biomarkers in ITx, and optimized selection of immunosuppressive therapies.
Objective
To determine whether vertical sleeve gastrectomy (VSG) attenuates fibrosis in mice on a high-fat high-cholesterol (HFHC) diet.
Background
Bariatric surgery mitigates non-alcoholic steatohepatitis in 85–90% of obese patients. While animal models demonstrate similar results on a high-fat diet, none have observed the effects of bariatric surgery on a combined HFHC diet.
Methods
Mice on a HFHC diet were used to confirm the development of hepatic fibrosis at 8 (n = 15) and 24 (n = 15) weeks. A separate cohort of mice on a HFHC diet for 12 weeks was subjected to either VSG (n = 18) or sham (n = 12) operations and remained on a HFHC diet for an additional 20 weeks. Changes in weight, dyslipidemia, and the development of steatosis and fibrosis were documented. Serum was obtained for bile acid analysis by liquid chromatography and mass spectrometry, while hepatic gene expression by RT-PCR was performed to evaluate intrahepatic lipid metabolism.
Results
Hepatic steatosis and fibrosis developed after 8 weeks on the HFHC diet. After VSG, mice demonstrated a sustained decrease in weight with a significant decrease in fibrosis compared to sham mice. Serum total cholesterol, HDL, and LDL were significantly reduced following surgery, while serum bile acids were significantly elevated. Intra-hepatic cholesterol excretion was not upregulated based on hepatic gene expression of CYP7A1 and ABCG5/8.
Conclusions
VSG attenuates the development of hepatic fibrosis in diet-induced obese mice, presumably through enhancement of cholesterol elimination at the intestinal level.
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