Melanocortin 1 receptor regulates cholesterol and bile acid metabolism in the liver

Abstract

Melanocortin 1 receptor (MC1-R) is widely expressed in melanocytes and leukocytes, and is thus strongly implicated in the regulation of skin pigmentation and inflammation. MC1-R mRNA has also been found in the rat and human liver, but its functional role has remained elusive. We hypothesized that MC1-R is functionally active in the liver and involved in the regulation of cholesterol and bile acid metabolism. We generated hepatocyte-specific MC1-R knock-out (L-Mc1r-/-) mice and phenotyped the mouse model for lipid profiles, liver histology and bile acid levels. L-Mc1r-/- mice had significantly increased liver weight, which was accompanied by elevated levels of total cholesterol and triglycerides in the liver as well as in the plasma. These mice demonstrated also enhanced liver fibrosis and a disturbance in bile acid metabolism as evidenced by markedly reduced bile acid levels in the plasma and feces. Mechanistically, using HepG2 cells as an in vitro model, we found that selective activation of MC1-R in HepG2 cells reduced cellular cholesterol content and enhanced uptake of low- and high-density lipoprotein particles via a cAMP-independent mechanism. In conclusion, the present results demonstrate that MC1-R signaling in hepatocytes regulates cholesterol and bile acid metabolism and its deficiency leads to hypercholesterolemia and enhanced lipid accumulation and fibrosis in the liver. Key words: Melanocortin 1 receptor; Cholesterol; Triglyceride; Bile acid; Steatosis; Fibrosis

Hepatocyte-specific loss of melanocortin 1 receptor disturbs fatty acid metabolism and promotes adipocyte hypertrophy

“…This view is also supported by previous studies, which have shown that MC1R activation does not have a signi cant effect on lipid metabolism in cultured adipocytes (17). Furthermore, our recent study revealed that hepatic MC1R signaling regulates cholesterol and bile acid metabolism in mice (19), indicating existence of functional MC1R in the liver.…”

“…Besides susceptibility for increased hepatic TG accumulation, Western diet-fed Mc1r LKO mice exhibited signs of enhanced liver brosis and in ammation as well as apoptosis. We had previously observed that selective activation of MC1R had no effect on in ammatory markers but reduced the expression of brosis-associated genes in cultured hepatocytes (19). In the current study, we extend this knowledge by showing that MC1R activation has some direct effects on apoptotic markers in primary hepatocytes.…”

“…Cell culture and primary mouse hepatocyte isolation HepG2 cells were used as an in vitro model to investigate the effects of MC1R activation as previously described (19). Brie y, HepG2 cell line (American Type Culture Collection, Rockville, MD, USA) was maintained in complete growth medium DMEM (Dulbecco's modi ed Eagle's medium; Sigma-Aldrich) supplemented with 10% (v/v) heat-inactivated fetal bovine serum (FBS; Thermo Fisher Scienti c, Gibco, MA, USA), 100 U/ml penicillin (Gibco), 100 µg/ml streptomycin (Gibco) at 37°C in a humid atmosphere with 5% CO2.…”

“…To test the hypothesis that MC1R de ciency in the liver triggers dyslipidemia and adipocyte hypertrophy, we employed hepatocyte-speci c MC1R knockout (Mc1r LKO) mice, as previously described (19), fed them Western diet for 12 weeks, and then phenotyped the mouse model in a comparable way as in Mc1r e/e mice. Mc1r LKO displayed a similar rate of weight gain throughout the entire feeding period in comparison with control mice (Fig.…”

TGR5 deficiency in excitatory neurons ameliorates Alzheimer’s pathology by regulating APP processing

“…BAs typically performs its function through BA receptors ( 36 ). The major forms of BA receptors (BA membrane receptors and nucleic receptors) were depicted in Fig.…”