ABSTRACT
BACKGROUND: Vertical sleeve gastrectomy (SGx) is a type of bariatric surgery to treat morbid obesity and metabolic dysfunction-associated steatotic liver disease (MASLD). The molecular mechanisms of SGx to improve MASLD are unclear, but increased bile acids (BAs) and FGF19 (mouse FGF15) were observed. FGF15/19 is expressed in the ileum in response to BAs and is critical in not only suppressing BA synthesis in the liver but also promoting energy expenditure. We hypothesized the reduction of obesity and resolution of MASLD by SGx may be mediated by FGF15/19. METHODS: First, we conducted hepatic gene expression analysis in obese patients undergoing SGx, with the results showing increased expression of FGF19 in obese patients' livers. Next, we used wild-type and intestine-specific Fgf15 knockout mice (Fgf15ile-/-) to determine the effects of FGF15 deficiency on improving the metabolic effects. RESULTS: SGx improved metabolic endpoints in both genotypes, evidenced by decreased obesity, improved glucose tolerance, and reduced MASLD progression. However, Fgf15ile-/- mice showed better improvement compared to wild-type mice after SGx, suggesting that other mediators than FGF15 are also responsible for the beneficial effects of FGF15 deficiency. Further gene expression analysis in brown adipose tissue suggests increased thermogenesis. CONCLUSIONS: FGF15 deficiency, the larger BA pool and higher levels of secondary BAs may increase energy expenditure in extrahepatic tissues, which may be responsible for improved metabolic functions following SGx.
Subject(s)
Fatty Liver , Fibroblast Growth Factors , Gastrectomy , Mice, Knockout , Obesity, Morbid , Fibroblast Growth Factors/genetics , Fibroblast Growth Factors/metabolism , Animals , Gastrectomy/methods , Mice , Obesity, Morbid/surgery , Obesity, Morbid/genetics , Obesity, Morbid/metabolism , Humans , Male , Fatty Liver/genetics , Fatty Liver/metabolism , Female , Bile Acids and Salts/metabolism , Liver/metabolism , Adult , Middle Aged , Bariatric Surgery , Mice, Inbred C57BLABSTRACT
Bile acids (BAs) are signaling molecules synthesized in the liver initially by CYP7A1 and CYP27A1 in the classical and alternative pathways, respectively. BAs are essential for cholesterol clearance, intestinal absorption of lipids, and endogenous modulators of farnesoid x receptor (FXR). FXR is critical in maintaining BA homeostasis and gut-liver crosstalk. Complex reactions in vivo and the lack of suitable animal models impede our understanding of the functions of individual BAs. In this study, we characterized the in vivo effects of three-day feeding of cholic acid (CA), deoxycholic acid (DCA), or ursodeoxycholic acid (UDCA) at physiological/non-hepatotoxic concentrations in a novel low-BA mouse model (Cyp7a1-/-/Cyp27a1-/-, DKO). Liver injury, BA levels and composition and BA signaling by the FXR-fibroblast growth factor 15 (FGF15) axis were determined. Overall, higher basal inflammation and altered lipid metabolism in DKO mice might be associated with low BAs. CA, DCA, and UDCA feeding activated FXR signals with tissue specificity. Dietary CA and DCA similarly altered tissue BA profiles to be less hydrophobic, while UDCA promoted a more hydrophobic tissue BA pool with the profiles shifted toward non-12α-OH BAs and secondary BAs. However, UDCA did not offer any overt protective effects as expected. These findings allow us to determine the precise effects of individual BAs in vivo on BA-FXR signaling and overall BA homeostasis in liver physiology and pathologies.
Subject(s)
Bile Acids and Salts , Cholic Acid , Fibroblast Growth Factors , Liver , Mice, Knockout , Receptors, Cytoplasmic and Nuclear , Animals , Receptors, Cytoplasmic and Nuclear/metabolism , Receptors, Cytoplasmic and Nuclear/genetics , Bile Acids and Salts/metabolism , Liver/metabolism , Liver/drug effects , Fibroblast Growth Factors/metabolism , Fibroblast Growth Factors/genetics , Cholic Acid/metabolism , Male , Mice, Inbred C57BL , Deoxycholic Acid/toxicity , Cholestanetriol 26-Monooxygenase/genetics , Cholestanetriol 26-Monooxygenase/metabolism , Mice , Ursodeoxycholic Acid/pharmacology , Signal Transduction/drug effects , Cholesterol 7-alpha-HydroxylaseABSTRACT
Chronic liver diseases encompass a wide spectrum of hepatic maladies that often result in cholestasis or altered bile acid secretion and regulation. Incidence and cost of care for many chronic liver diseases are rising in the United States with few Food and Drug Administration-approved drugs available for patient treatment. Farnesoid X receptor (FXR) is the master regulator of bile acid homeostasis with an important role in lipid and glucose metabolism and inflammation. FXR has served as an attractive target for management of cholestasis and fibrosis; however, global FXR agonism results in adverse effects in liver disease patients, severely affecting quality of life. In this review, we highlight seminal studies and recent updates on the FXR proteome and identify gaps in knowledge that are essential for tissue-specific FXR modulation. In conclusion, one of the greatest unmet needs in the field is understanding the underlying mechanism of intestinal versus hepatic FXR function.
Subject(s)
Cholestasis , Liver Diseases , Humans , Friends , Quality of Life , Liver/metabolism , Cholestasis/drug therapy , Liver Diseases/drug therapy , Liver Diseases/metabolism , Bile Acids and Salts/metabolismABSTRACT
Alzheimer's disease (AD) is a progressive neurodegenerative disorder that accounts for approximately 60-80% of dementia cases worldwide and is characterized by an accumulation of extracellular senile plaques composed of ß-amyloid (Aß) peptide and intracellular neurofibrillary tangles (NFTs) containing hyperphosphorylated tau protein. Sporadic or late-onset AD (LOAD) represents 95 % of the AD cases and its etiology does not appear to follow Mendelian laws of inheritance, thus, implicating the role of epigenetic programming and environmental factors. Apolipoprotein allele 4 (ApoE4), the only established genetic risk factor for LOAD, is suggested to accelerate the pathogenesis of AD by increasing tau hyperphosphorylation, inhibiting the clearance of amyloid-ß (Aß), and promoting Aß aggregation. Perfluorooctanesulfonic acid (PFOS) is a persistent organic pollutant, with potential neurotoxic effects, that poses a major threat to the ecosystem and human health. By employing in vivo and in vitro models, the present study investigated PFOS as a potential risk factor for LOAD by assessing its impact on amyloidogenesis, tau pathology, and rodent behavior. Our behavioral analysis revealed that developmentally exposed male and female mice exhibited a strong trend of increased rearing and significantly increased distance traveled in the open field test. Biochemically, GSK3ß and total ApoE were increased following developmental exposure, in vivo. Furthermore, in vitro, low concentrations of PFOS elevated protein levels of APP, tau, and its site-specific phosphorylation. Differentiated SH-SY5Y cells exposed to a series of PFOS concentrations, also, had elevated protein expression of GSK3ß. These data suggest that total ApoE is inducible by environmental exposure to PFOS.