Reduced absorption of saturated fatty acids and resistance to diet-induced obesity and diabetes by ezetimibe-treated and Npc1l1-/- mice

Am J Physiol Gastrointest Liver Physiol. 2008 Oct;295(4):G776-83. doi: 10.1152/ajpgi.90275.2008. Epub 2008 Aug 21.

Abstract

The impact of NPC1L1 and ezetimibe on cholesterol absorption are well documented. However, their potential consequences relative to absorption and metabolism of other nutrients have been only minimally investigated. Thus studies were undertaken to investigate the possible effects of this protein and drug on fat absorption, weight gain, and glucose metabolism by using Npc1l1(-/-) and ezetimibe-treated mice fed control and high-fat, high-sucrose diets. Results show that lack of NPC1L1 or treatment with ezetimibe reduces weight gain when animals are fed a diabetogenic diet. This resistance to diet-induced obesity results, at least in part, from significantly reduced absorption of dietary saturated fatty acids, particularly stearate and palmitate, since food intake did not differ between groups. Expression analysis showed less fatty acid transport protein 4 (FATP4) in intestinal scrapings of Npc1l1(-/-) and ezetimibe-treated mice, suggesting an important role for FATP4 in intestinal absorption of long-chain fatty acids. Concomitant with resistance to weight gain, lack of NPC1L1 or treatment with ezetimibe also conferred protection against diet-induced hyperglycemia and insulin resistance. These unexpected beneficial results may be clinically important, given the focus on NPC1L1 as a target for the treatment of hypercholesterolemia.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Azetidines / pharmacology*
  • Diabetes Mellitus / etiology*
  • Diabetes Mellitus / prevention & control
  • Dietary Carbohydrates / administration & dosage*
  • Dietary Fats / administration & dosage*
  • Ezetimibe
  • Fatty Acid Transport Proteins / biosynthesis
  • Fatty Acids / metabolism*
  • Female
  • Hyperglycemia / prevention & control
  • Intestinal Absorption / physiology*
  • Male
  • Membrane Transport Proteins / deficiency*
  • Membrane Transport Proteins / physiology
  • Mice
  • Obesity / prevention & control*

Substances

  • Azetidines
  • Dietary Carbohydrates
  • Dietary Fats
  • Fatty Acid Transport Proteins
  • Fatty Acids
  • Membrane Transport Proteins
  • Npc1l1 protein, mouse
  • Slc27a4 protein, mouse
  • Ezetimibe