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Published on: September 9, 2021
Acceleration of biliary cholesterol secretion restores glycemic control and alleviates hypertriglyceridemia in obese
Kai Su1, Nadezhda S Sabeva, Yuhuan Wang
1From the Department of Pharmaceutical Sciences, Graduate Center for Nutritional Sciences and Saha Cardiovascular Research Center, University of Kentucky, Lexington (K.S., Y.W., X.L., J.D.L., G.A.G.); Department of Neuroscience, Universidad Central del Caribe, Bayamon, Puerto Rico (N.S.S.); Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas (J.L.); and Department of Clinical Laboratories, Jinshan Branch of the Sixth People's Hospital of Shanghai, Shanghai, China (S.L.).
Objective:
Recent studies support a role for cholesterol in the development of obesity and nonalcoholic fatty liver disease. Mice lacking the ABCG5 ABCG8 (G5G8) sterol transporter have reduced biliary cholesterol secretion and are more susceptible to steatosis, hepatic insulin resistance, and loss of glycemic control when challenged with a high-fat diet. We hypothesized that accelerating G5G8-mediated biliary cholesterol secretion would correct these phenotypes in obese mice.
Approach And Results:
Obese (db/db) male and their lean littermates were administered a cocktail of control adenovirus or adenoviral vectors encoding ABCG5 and ABCG8 (AdG5G8). Three days after viral administration, measures of lipid and glucose homeostasis were determined, and tissues were collected for biochemical analyses. AdG5G8 increased biliary cholesterol and fecal sterol elimination. Fasting glucose and triglycerides declined, and glucose tolerance improved in obese mice expressing G5G8 compared with mice receiving control adenovirus. These changes were associated with a reduction in phosphorylated eukaryotic initiation factor 2α and c-Jun N-terminal kinase in liver, suggesting alleviation of endoplasmic reticulum stress. Phosphorylated insulin receptor and protein kinase B were increased, indicating restored hepatic insulin signaling. However, there was no reduction in hepatic triglycerides after the 3-day treatment period.
Conclusions:
Accelerating biliary cholesterol secretion restores glycemic control and reduces plasma triglycerides in obese db/db mice.
Insights
Accelerating cholesterol secretion via ABCG5/ABCG8 transporters improved glucose control and lowered triglycerides in obese mice. This suggests a therapeutic potential for managing metabolic dysfunction in obesity.
Area of Science:
- Metabolic disease research
- Hepatology
- Molecular endocrinology
Background:
- Cholesterol plays a role in obesity and nonalcoholic fatty liver disease.
- Mice lacking ABCG5/ABCG8 sterol transporters show impaired biliary cholesterol secretion, leading to increased susceptibility to steatosis and insulin resistance.
- High-fat diets exacerbate these metabolic defects.
Purpose of the Study:
- To investigate if enhancing ABCG5/ABCG8-mediated biliary cholesterol secretion can correct metabolic phenotypes in obese mice.
- To determine the effects of accelerated cholesterol secretion on glucose and lipid homeostasis.
- To explore the impact on endoplasmic reticulum stress and hepatic insulin signaling.
Main Methods:
- Obese (db/db) mice and lean littermates were treated with adenoviral vectors encoding ABCG5 and ABCG8 (AdG5G8) or control adenovirus.
- Biliary cholesterol secretion and fecal sterol elimination were measured.
- Glucose tolerance, fasting glucose, and triglyceride levels were assessed.
- Liver tissues were analyzed for markers of endoplasmic reticulum stress and insulin signaling.
Main Results:
- AdG5G8 treatment significantly increased biliary cholesterol and fecal sterol elimination.
- Obese mice receiving AdG5G8 showed reduced fasting glucose and triglycerides, with improved glucose tolerance.
- Hepatic endoplasmic reticulum stress markers decreased, and insulin signaling markers increased.
- No reduction in hepatic triglycerides was observed within the 3-day treatment period.
Conclusions:
- Accelerating biliary cholesterol secretion effectively restores glycemic control in obese mice.
- This approach also reduces plasma triglycerides in obese db/db mice.
- Enhancing ABCG5/ABCG8 function presents a potential strategy for treating metabolic disorders associated with obesity.
