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Regulation of liver energy balance by nuclear receptors
Author(s) -
Moore David D
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.103.1
Subject(s) - farnesoid x receptor , endocrinology , medicine , autophagy , cholestasis , nuclear receptor , biology , ketogenesis , bile acid , peroxisome proliferator activated receptor , catabolism , cyp8b1 , receptor , cholesterol 7 alpha hydroxylase , transcription factor , biochemistry , metabolism , ketone bodies , apoptosis , gene
The liver is crucial for maintaining whole body energy balance. For example, the liver responds to fasting by secreting glucose and to feeding by storing it as glycogen. In response to overnutrition, the liver stores excess fat, which is correlated with insulin resistance. The nuclear receptors FXR and PPARα are activated in the fed or fasted liver, respectively, and regulate many metabolic processes. Among such processes, autophagy is a catabolic pathway that recycles nutrients upon starvation and maintains cellular energy homeostasis. We have found that both FXR and PPARα regulate hepatic autophagy. Pharmacologic activation of the bile acid receptor FXR strongly suppresses the induction of autophagy in the fasting state, while pharmacologic activation of PPARα reverses the normal suppression of autophagy in the fed state, inducing autophagic lipid degradation, or lipophagy. Neonatal cholestasis is a potentially life‐threatening condition. We have identified four individuals from two unrelated families with neonatal cholestasis and mutations in NR1H4 , which encodes the bile acid receptor FXR. Clinical features of NR1H4 ‐related cholestasis include neonatal onset with rapid progression to end‐stage liver disease, vitamin‐K independent coagulopathy, low‐to‐normal serum gamma‐glutamyl transferase activity, elevated serum alpha‐fetoprotein, and undetectable liver bile salt export pump ( ABCB11 ) expression. The coagulopathy is due to FXR transcriptional regulation of multiple components of the coagulation pathway. Genome wide binding studies indicate that FXR may also regulate a number of other liver secreted proteins. The process of secretion is very energy intensive, and it is well known that fasting suppresses secretion via post‐transcriptional mechanisms. We suggest that nuclear receptors also provide nutrient sensitive transcriptional input to liver secretion, with FXR licensing this process while PPARα suppresses it. Overall, we conclude that nuclear receptors act via complementary, interlocking mechanisms to maintain proper energy balance in the liver.