Depletion of hepatic forkhead box O1 does not affect cholelithiasis in male and female mice

J Biol Chem. 2020 May 15;295(20):7003-7017. doi: 10.1074/jbc.RA119.012272. Epub 2020 Apr 9.


Cholelithiasis is one of the most prevalent gastroenterological diseases and is characterized by the formation of gallstones in the gallbladder. Both clinical and preclinical data indicate that obesity, along with comorbidity insulin resistance, is a predisposing factor for cholelithiasis. Forkhead box O1 (FoxO1) is a key transcription factor that integrates insulin signaling with hepatic metabolism and becomes deregulated in the insulin-resistant liver, contributing to dyslipidemia in obesity. To gain mechanistic insights into how insulin resistance is linked to cholelithiasis, here we determined FoxO1's role in bile acid homeostasis and its contribution to cholelithiasis. We hypothesized that hepatic FoxO1 deregulation links insulin resistance to impaired bile acid metabolism and cholelithiasis. To address this hypothesis, we used the FoxO1LoxP/LoxP-Albumin-Cre system to generate liver-specific FoxO1-knockout mice. FoxO1-knockout mice and age- and sex-matched WT littermates were fed a lithogenic diet, and bile acid metabolism and gallstone formation were assessed in these animals. We showed that FoxO1 affected bile acid homeostasis by regulating hepatic expression of key enzymes in bile acid synthesis and in biliary cholesterol and phospholipid secretion. Furthermore, FoxO1 inhibited hepatic expression of the bile acid receptor farnesoid X receptor and thereby counteracted hepatic farnesoid X receptor signaling. Nonetheless, hepatic FoxO1 depletion neither affected the onset of gallstone disease nor impacted the disease progression, as FoxO1-knockout and control mice of both sexes had similar gallstone weights and incidence rates. These results argue against the notion that FoxO1 is a link between insulin resistance and cholelithiasis.

Keywords: FOXO; FoxO1; bile acid; bile acid metabolism; cholelithiasis; farnesoid X receptor (Fxr); forkhead box O1 (FoxO1); gallstone; gene knockout; insulin resistance; liver; metabolic disease; metabolic disorder; mice; obesity.

Publication types

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

MeSH terms

  • Animals
  • Bile Acids and Salts / genetics
  • Bile Acids and Salts / metabolism*
  • Cholesterol / genetics
  • Cholesterol / metabolism
  • Female
  • Forkhead Box Protein O1 / genetics
  • Forkhead Box Protein O1 / metabolism*
  • Gallstones / genetics
  • Gallstones / metabolism*
  • Gene Deletion
  • Gene Expression Regulation
  • Insulin Resistance*
  • Liver
  • Male
  • Mice
  • Mice, Transgenic
  • Organ Specificity
  • Phospholipids / genetics
  • Phospholipids / metabolism
  • Receptors, Cytoplasmic and Nuclear / biosynthesis
  • Receptors, Cytoplasmic and Nuclear / genetics
  • Signal Transduction*


  • Bile Acids and Salts
  • Forkhead Box Protein O1
  • Foxo1 protein, mouse
  • Phospholipids
  • Receptors, Cytoplasmic and Nuclear
  • farnesoid X-activated receptor
  • Cholesterol