Understanding bile acid and lipid metabolism for novel treatment strategies of hyperlipidemia and diabetes type 2
Description: Lipid disorders are linked to diseases such as heart disease, diabetes, malabsorption and gallstone disease. The current project aims to improve our knowledge as regards how bile acids and bile acid synthesis in the liver affects lipid and sugar metabolism. It is long known that the bile acid sequestrant cholestyramine often increases plasma triglycerides, however the mechanism underlying this is still unclear. For this purpose we study the acute temporal effects elicited after the ingestion of the bile acid sequestrant cholestyramine to healthy subjects. To evaluate the importance of cholesterol and bile acid deficiency subjects are also studied during combined therapy with cholestyramine and a potent statin to further reduce substrate levels for bile acid synthesis. Bile acid and cholesterol synthesis are monitored using plasma markers C4 and lathosterol.
Another approach we use to study the link between bile acid synthesis and plasma triglycerides is from an initial screening of a healthy cohort for bile acid synthesis and triglycerides. From one index case we sampled the entire family and relatives (14 subjects). We have identified a family with inherited high bile acid synthesis (5-fold increase) with modestly elvated plasma triglycerides in 4 of the 14 members. Subsequent exome sequencing have now identified a mutation in a gene for a protein that is not expressed in the mouse. We are now investigating the function of this protein. The future identification of a possible novel mode of regulation of human bile acid synthesis can not be underestimated in particular since this appears linked to the level of plasma triglycerides.
Another section of the project concerns diabetes type 2, an emerging global health problem largely underpinned by overeating in combination with low physical activity. Sustainable methods to reduce food intake have proven very difficult. We have found that mouse bile acids reduce body weight and the development of diabetes type 2 in mice fed a classic high-fat diet. This is likely partly due to that the absorption of nutrients from the intestine is reduced but also to the release into the blood of powerful intestinal hormones such as GLP-1. Presumably also mechanisms inducing satiety and thereby reduced food intake may appear. Studies are now in progress to in detail scrutinize the metabolic responses that mouse bile acids elicit to deeper understand why they are antidiabetogenic and lower body weight. Also the yet unknown metabolic pathways for the synthesis of mouse bile acids are investigated with the aim to identify the enzyme/s responsible for their formation. Humans do not normally make mouse bile acids but have very high levels of the precursor bile acid chenodeoxycholic acid. Oral treatment with mouse bile acids or stimulation of mouse bile acid production in humans in the future may thus create a state of internal dietary restriction at the intestinal level that may be feasible to reduce body weight and particularly to improve the resistance against the development of type 2 diabetes.
Funder: Vetenskapsrådet
Amount: SEK 2,100,000
Funding type: research
Funder scheme: Project grant
Start date: 2016-01-01
End date: 2018-12-31
Investigator: Mats Rudling
Institution: Karolinska Institutet
Funded outputs count: 4
Funder award ID: 2015-02781
OpenAlex ID: G7711954582