Pathophysiological importance of bile cholesterol reabsorption: hepatic NPC1L1-exacerbated steatosis and decreasing VLDL-TG secretion in mice fed a high-fat diet View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2019-12-28

AUTHORS

Yu Toyoda, Tappei Takada, Yoshihide Yamanashi, Hiroshi Suzuki

ABSTRACT

BackgroundNon-alcoholic fatty liver disease (NAFLD) is one of the most common liver diseases worldwide, although its pathogenesis remains to be elucidated. A recent study revealed that hepatic Niemann-Pick C1-Like 1 (NPC1L1), a cholesterol re-absorber from bile to the liver expressed on the bile canalicular membrane, is an exacerbation factor of NAFLD. Indeed, transgenic mice with hepatic expression of human NPC1L1 under a liver-specific promoter (L1-Tg mice) developed steatosis with a high-fat diet (HFD) containing cholesterol within a few weeks. However, the mechanism underlying diet-induced hepatic NPC1L1-mediated lipid accumulation is poorly defined.MethodsTo achieve a deeper understanding of steatosis development in L1-Tg mice, the biochemical features of hepatic NPC1L1-mediated steatosis were investigated. Hemizygous L1-Tg mice and wild-type littermate controls fed a HFD or control-fat diet were used. At the indicated time points, the livers were evaluated for cholesterol and triglyceride (TG) contents as well as mRNA levels of hepatic genes involved in the maintenance of lipid homeostasis. The hepatic ability to secrete very low-density lipoprotein (VLDL)-TG was also investigated.ResultsUnlike the livers of wild-type mice that have little expression of hepatic Npc1l1, the livers of L1-Tg mice displayed time-dependent changes that indicated steatosis formation. In steatosis, there were three different stages of development: mild accumulation of hepatic cholesterol and TG (early stage), acceleration of hepatic TG accumulation (middle stage), and further accumulation of hepatic cholesterol (late stage). In the early stage, between WT and L1-Tg mice fed a HFD for 2 weeks, there were no significant differences in the hepatic expression of Pparα, Acox1, Fat/Cd36, Srebf1, and Srebf2; however, the hepatic ability to secrete VLDL-TG decreased in L1-Tg mice (P < 0.05). Furthermore, this decrease was completely prevented by administration of ezetimibe, an NPC1L1-selective inhibitor.ConclusionHepatic NPC1L1 exacerbates diet-induced steatosis, which was accompanied by decreased hepatic ability of VLDL-TG secretion. The obtained results provide a deeper understanding of L1-Tg mice as a promising NAFLD animal model that is able to re-absorb biliary-secreted cholesterol similar to humans. Furthermore, this work supports further studies of the pathophysiological impact of re-absorbed biliary cholesterol on the regulation of hepatic lipid homeostasis. More... »

PAGES

234

Identifiers

URI

http://scigraph.springernature.com/pub.10.1186/s12944-019-1179-0

DOI

http://dx.doi.org/10.1186/s12944-019-1179-0

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1123710043

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/31883528


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93 hepatic Niemann-Pick C1
94 hepatic TG accumulation
95 hepatic ability
96 hepatic cholesterol
97 hepatic expression
98 hepatic genes
99 hepatic lipid homeostasis
100 high-fat diet
101 homeostasis
102 human NPC1L1
103 humans
104 impact
105 importance
106 inhibitors
107 levels
108 lipid accumulation
109 lipid homeostasis
110 lipoprotein
111 littermate controls
112 little expression
113 liver
114 liver disease
115 liver-specific promoter
116 low-density lipoprotein
117 mRNA levels
118 maintenance
119 mechanism
120 membrane
121 mice
122 mild accumulation
123 model
124 pathogenesis
125 pathophysiological impact
126 pathophysiological importance
127 point
128 promoter
129 reabsorption
130 regulation
131 results
132 secretion
133 significant differences
134 stage
135 steatosis
136 steatosis development
137 steatosis formation
138 study
139 time points
140 time-dependent changes
141 transgenic mice
142 triglyceride content
143 understanding
144 weeks
145 wild-type littermate controls
146 wild-type mice
147 work
148 wt
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