Dietary cholesterol reverses resistance to diet-induced weight gain in mice lacking Niemann-Pick C1-Like 1

Yinyan Ma,Liqing Yu,Lin Jia,George Liu

doi:10.1194/jlr.m008599

Yinyan Ma, Liqing Yu + Show 2 more

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https://doi.org/10.1194/jlr.m008599

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Abstract

Niemann-Pick C1-Like 1 (NPC1L1) mediates intestinal cholesterol absorption. NPC1L1 knockout (L1-KO) mice were recently shown to be resistant to high-fat diet (HFD)-induced obesity in one study, which was contrary to several other studies. Careful comparison of dietary compositions in these studies implies a potential role of dietary cholesterol in regulating weight gain. To examine this potential, wild-type (WT) and L1-KO mice were fed one of three sets of diets for various durations: (1) a HFD without added cholesterol for 5 weeks; (2) a high-carbohydrate diet with or without added cholesterol for 5 weeks; or (3) a synthetic HFD with or without added cholesterol for 18 weeks. We found that L1-KO mice were protected against diet-induced weight gain only on a diet without added cholesterol but not on a diet containing 0.16% or 0.2% (w/w) cholesterol, an amount similar to a typical Western diet, regardless of the major energy source of the diet. Food intake and intestinal fat absorption were similar between the two genotypes. Intestinal cholesterol absorption was blocked, and fecal cholesterol excretion increased in L1-KO mice. Under all diets, L1-KO mice were protected from hepatosteatosis. In conclusion, increasing dietary cholesterol restores diet-induced weight gain in mice deficient in NPC1L1-dependent cholesterol absorption.

Highlights

Niemann-Pick C1-Like 1 (NPC1L1) mediates intestinal cholesterol absorption
The reduced body weight gain in L1-KO mice was associated with a 66% decrease in epididymal fat weight and a modest but significant decrease in liver weight compared with WT mice (Table 1)
Our data show that increasing dietary cholesterol can raise plasma and liver cholesterol in mice deficient in intestinal cholesterol absorption, such as L1-KO mice, though to a much lesser extent compared with WT mice (Table 3)

Summary

Introduction

Niemann-Pick C1-Like 1 (NPC1L1) mediates intestinal cholesterol absorption. NPC1L1 knockout (L1-KO) mice were recently shown to be resistant to high-fat diet (HFD)-induced obesity in one study, which was contrary to several other studies. In addition to de novo biosynthesis and hepatobiliary secretion, intestinal absorption of cholesterol is another major pathway by which the body regulates cholesterol homeostasis in response to fluctuations in cholesterol availability and utilization Inhibiting this pathway by a cholesterol absorption inhibitor ezetimibe (trade name Zetia) [1] has been shown to significantly reduce plasma total and low-density lipoprotein cholesterol in all mammalian species tested, including humans [2,3,4,5,6,7,8,9]. The potency of low doses of ezetimibe in inhibiting intestinal cholesterol absorption strongly supports the notion that intestinal cholesterol absorption is an active and protein-mediated process The search for this protein resulted in identification of Niemann-Pick C1-Like 1 (NPC1L1) as a cholesterol transporter essential for intestinal cholesterol absorption [14].

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