Dietary cholesterol directly induces acute inflammasome-dependent intestinal inflammation.

Abstract

Prolonged ingestion of a cholesterol- or saturated fatty acid-enriched diet induces chronic, often systemic, auto-inflammatory responses resulting in significant health problems worldwide. In vivo information regarding the local and direct inflammatory effect of these dietary components in the intestine and, in particular, on the intestinal epithelium is lacking. Here we report that both mice and zebrafish exposed to high-fat (HFDs) or high-cholesterol (HCDs) diets develop acute innate inflammatory responses within hours, reflected in the localized interleukin-1β-dependent accumulation of myeloid cells in the intestine. Acute HCD-induced intestinal inflammation is dependent on cholesterol uptake via Niemann-Pick C1-like 1 and inflammasome activation involving apoptosis-associated Speck-like protein containing a caspase recruitment domain, which leads to Caspase-1 activity in intestinal epithelial cells. Extended exposure to HCD results in localized, inflammation-dependent, functional dysregulation as well as systemic pathologies. Our model suggests that dietary cholesterol initiates intestinal inflammation in epithelial cells.

• Authors: Fränze Progatzky, Navjyot J Sangha, Nagisa Yoshida, Marie McBrien, Jackie Cheung, Alice Shia, James Scott, Julian R Marchesi, Jonathan R Lamb, Laurence Bugeon, Margaret J Dallman
• Journal: Nature communications (Nat Commun) Vol. 5 Pg. 5864 (Dec 23 2014) ISSN: 2041-1723 [Electronic] England
• PMID: 25536194 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 3-benzyl-7-(2-benzoxazolyl)thio-1,2,3-triazolo(4,5-d)pyrimidine
• Benzoxazoles
• Carrier Proteins
• Cholesterol, Dietary
• Fatty Acids
• Inflammasomes
• Interleukin-1beta
• Membrane Transport Proteins
• NF-kappa B
• NLR Family, Pyrin Domain-Containing 3 Protein
• Nlrp3 protein, mouse
• Npc1l1 protein, mouse
• Triazoles
• Caspase 1

Topics

• Animals
• Benzoxazoles (pharmacology)
• Carrier Proteins (genetics, immunology)
• Caspase 1 (genetics, immunology)
• Cholesterol, Dietary (adverse effects)
• Diet, High-Fat
• Fatty Acids (metabolism)
• Fatty Liver (etiology, genetics, immunology, pathology)
• Female
• Immunity, Innate
• Inflammasomes (drug effects)
• Inflammation (etiology, genetics, immunology, pathology)
• Interleukin-1beta (biosynthesis, metabolism)
• Intestinal Mucosa (immunology, pathology)
• Intestines (immunology, pathology)
• Membrane Transport Proteins (genetics, immunology)
• Mice
• Mice, Inbred BALB C
• Myeloid Cells (immunology, pathology)
• NF-kappa B (genetics, immunology)
• NLR Family, Pyrin Domain-Containing 3 Protein
• Triazoles (pharmacology)
• Zebrafish