Abstract
Dietary interventions such as prolonged calorie restriction (CR) and intermittent fasting provide health benefits including a reduction in the inflammatory burden and regulation of energy metabolism. During CR, β-hydroxybutyrate (BHB) level is elevated in the serum. BHB is a ligand of GPR109A, which inhibits lipolysis and exerts anti-inflammatory effects on cells. During aging, comorbidities related to dyslipidemia are significantly associated with fatty liver. However, the underlying mechanisms of BHB in hepatic ER stress and dyslipidemia are unclear and remain to be elucidated. Here, we used aged rats that were administered with BHB and compared the modulatory effects of BHB through the GPR109A/AMPK pathway on the hepatic endoplasmic reticulum (ER) stress and lipid accumulation to CR rats. BHB caused suppression of hepatic ER stress and lipid accumulation through GPR109A/AMPK pathway in the aged rats. Aged rats of both treatment groups showed reduced cAMP level and PKA phosphorylation. Furthermore, AMPK-Ser173 phosphorylation via PKA was decreased, whereas AMPK-Thr172 phosphorylation was increased by BHB and CR. Further supporting evidence was provided in HepG2 cells that BHB inhibited ER stress and lipid accumulation induced by palmitate. These results suggest that BHB activates GPR109A and regulates the activation of AMPK. These findings were further confirmed by GPR109A-siRNA transfection in vitro. In addition, BHB treatment elevated the protein levels of AMPK leading to significant inhibition of hepatic steatosis, whereas AMPK-siRNA treatment abolished these effects. Taken together, these findings suggest that BHB could be a effective molecule that mimics CR in ameliorating age-related hepatic lipid accumulation via GPR109A signaling pathway.
Highlights
Dyslipidemia is a pathological condition commonly characterized by increased serum triglycerides (TGs) and low-density lipoprotein (LDL) levels along with decreased high-density lipoprotein (HDL) cholesterol level [1]
Endoplasmic reticulum (ER) stress is defined as a disturbance of ER homeostasis that leads to an impaired protein synthesis process leading to accumulation of unfolded and misfolded proteins in the ER lumen that triggers an ER stress response or unfolded protein response (UPR) signaling pathway
Fatty liver disease is considered to be the consequence of metabolic diseases accompanied by increased serum free fatty acids (FFAs), TG, and LDL levels, as well as decreased HDL level
Summary
Dyslipidemia is a pathological condition commonly characterized by increased serum triglycerides (TGs) and low-density lipoprotein (LDL) levels along with decreased high-density lipoprotein (HDL) cholesterol level [1] These abnormalities of lipid metabolism are influenced by dysfunctions of the liver in maintaining metabolic homeostasis [2]. The molecular mechanisms of how CR and β-hydroxybutyrate (BHB) delay aging-related liver ER stress need to be further investigated. Understanding these mechanisms is of great importance as this could lead to the identification of new therapeutic targets for age-associated ER stress and hepatic lipid metabolism. AMPK stimulates glucose uptake and FA oxidation in the liver, whereas it inhibits gluconeogenesis and synthesis of cholesterol, FA, and protein [20]
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