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Chewing the fat: a mechanistic link between cholesterol and colon cancer
Wang B, Rong X, Palladino END, et al. Phospholipid remodelling and cholesterol availability regulate intestinal stemness and tumorigenesis. Cell Stem Cell 2018;22:206–20.
Excess dietary lipids are linked to an increased risk of colon cancer, but the mechanism is unclear. Wang and colleagues found that stimulating cholesterol biosynthesis in mice increased intestinal stem cell proliferation and neoplasia. Phospholipid and cholesterol, crucial components of cell membranes, act as signalling molecules. To determine whether they affect stem cell function, a gene regulating phospholipid metabolism was deleted in mice. Lysophosphatidylcholine acetyl-transferase 3 (Lpcat3) incorporates polyunsaturated fatty acids into phospholipids. Mice with intestine-specific Lpcat3 deficiency developed intestinal hypertrophy, with a threefold increase in proliferating cells. Immunostaining confirmed an increase in both stem cells and progenitor cells. Ex vivo, deletion of Lpcat3 increased the size, number and complexity of organoids generated from intestinal crypts. This was counteracted by addition of liposomes containing polyunsaturated lipids. Gene expression profiling of Lpcat3-deficient crypts showed enrichment of genes involved in sterol biosynthesis. Free cholesterol was also higher in these crypts, indicating cholesterol biosynthesis and total cholesterol level is coupled to phospholipid remodelling. Blocking cholesterol biosynthesis pharmacologically inhibited Lpcat-deficient organoid growth and reduced intestinal hypertrophy in mice. Wild-type mice fed a diet high in cholesterol also showed increased cell proliferation, proving that cholesterol acts as a direct mitogen for intestinal stem cells. Finally, Lpcat3 deletion in adenomatous polyposis coli mutant (APCMin) mice, which are predisposed to intestinal tumorigenesis, exacerbated tumour burden 10-fold and decreased survival. In summary, this study revealed a link between phospholipid remodelling and cholesterol biosynthesis and the contribution of this axis to tumourigenesis.
Aortic carbocypeptidase-like protiein (ACLP) represents a novel antifibrotic therapeutic target in non-alcoholic fatty liver disease (NAFLD)
Teratani T, Tomita K, Suzuki T, et al. Aortic carboxypeptidase-like protein, a WNT ligand, exacerbates nonalcoholic steatohepatitis. J Clin Invest 2018;128:1581–96.
A greater understanding of the pathophysiology of liver fibrosis in NAFLD may yield …
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