Unexpected effects of fasting on murine lipid homeostasis – Transcriptomic and lipid profiling

Background & Aims

Starvation induces massive perturbations in metabolic pathways involved in energy metabolism, but its effect on the metabolism of lipids, particularly cholesterol, is little understood.

Methods

A comparative genomic analysis of the gut and the liver in response to fasting was performed, with intestinal perfusion and lipid profiling of the plasma, bile, liver, intestinal tissue, perfusate, and faeces in FVB mice.

Results

The expression profiles suggested increased cholesterol trafficking in the liver and decreased trafficking in the small intestine. Plasma cholesterol concentrations significantly increased, and triglycerides decreased in fasting. Surprisingly, in prolonged fasting, the biliary bile salt and lipid output rates increased, with increased hepatic and intestinal lipid turnover, and enhanced trans-intestinal cholesterol excretion. In contrast, faecal sterol loss declined sharply. To investigate whether the increased biliary phospholipid secretion could nourish the intestinal epithelium, we studied the histology of the small intestines upon fasting in multidrug resistant protein 2 deficient mice with scarce biliary phospholipids. Their adaptive biliary response to fasting was lost, while the shortage of biliary phospholipids strongly induced apoptosis and proliferation in the small intestine and increased the number of mucin-producing cells.

Conclusion

Even with no dietary fat, lipid levels remain remarkably constant in the murine liver and intestines during prolonged fasting. The biliary system, always assumed to be coupled to the postprandial response, shows a paradoxical increase in activity. We hypothesise that biliary lipids are mobilised to supply the enterocytes with luminal fuel and to stabilise transport systems in the intestine for ensuring a rapid recovery when the food supply resumes.

Abbreviations: PPARα, peroxisome proliferator-activated receptor α, TG, triglyceride, PL, phospholipids, FFA, free fatty acid, VLDL, very low density lipoprotein, BS, bile salts, TICE, trans-intestinal cholesterol excretion, HA, haematoxyline azophloxine, PNCA, proliferating-cell nuclear antigen, GO, gene ontology, GEO, gene expression omnibus, SEM, standard error of the mean, SREBP, sterol regulatory element binding protein, LXRα, liver X receptor α, SRBI, scavenger receptor BI, NPC1l1, Niemann–Pick C1-like 1, APOA4, apolipoprotein A4, ACAT1, acetyl-CoA acetyltransferase, MVK, mevalonate kinase, CYP39A1, cytochrome P450, 39A1, CYP7B1, cytochrome P450, 7B1, HMGCR, 3-hydroxy-3-methylglutaryl-coenzyme A reductase, HMGCS2, 3-hydroxy-3-methylglutaryl-coenzyme A synthase 2, BW, body weight, TC, taurocholate, PC, phosphatidylcholine, WT, wild type

Keywords: Starvation response, Lipid homeostasis, Expression profiling, Trans-intestinal cholesterol excretion, Faecal sterols