Abstract :
[en] Dysregulated lipid and cholesterol metabolism is associated with various metabolic diseases and even cancers. The liver is a critical organ for lipid and cholesterol metabolism. Previous evidence suggests that gut microbiota is associated with lipid and cholesterol metabolism, but little is known about the specific effects of gut microbiota on hepatic lipid and cholesterol biosynthesis. This dissertation investigated the comprehensive influence of gut microbiota on hepatic lipid metabolism and also explored the mechanism by which the gut microbiota modulates hepatic cholesterol biosynthesis.
The first study was aimed to comprehensively evaluate the effects of gut microbiota on hepatic lipid metabolism. Using a pseudo-germ-free mouse model constructed by an antibiotics cocktail (Abx), we found that Abx treatment for 5 weeks successfully decreased the gut microbiota, accompanied by a reduced amount of microbial synthesized components (Lipopolysaccharides (LPS)) and metabolites (butyrate and isovalerate) in mice fed a high fat diet (HFD). This depletion of microbiota decreased their body weight. Meanwhile, gut microbiota depletion lowered the serum levels of glucose, total cholesterol (TC), low-density lipoproteins (LDL), insulin, and leptin. Moreover, microbiota depletion inhibited the fat deposition in both white adipose tissue and liver. As for the mechanism, RNA-seq results showed that gut microbiota depletion altered the expression of hepatic genes involved in fatty acid and cholesterol metabolism such as fatty acid translocase (Cd36), monoacylglycerol o-acyltransferase 1 (Mogat1), cytochrome P450 family 39 subfamilies A polypeptide 1 (Cyp39a1), ATP-binding cassette subfamily C member 3 (Abcc3), and Acyl-CoA:glycerol-3-phosphate acyltransferase (Gpat3). In addition, mice with microbial depletion exhibited lower relative abundance of bacteria related to abnormal metabolism and inflammation, including Lachnospiraceae, Coriobacteriaceae_UCG-002, Enterorhabdus, Faecalibaculum, and Desulfovibrio. Furthermore, a correlation analysis revealed strong associations between the altered gut microbiota and serum cholesterol level. These findings suggest that the gut microbiota plays an important role in the lipid and cholesterol metabolism.
The second study further investigated the underlying mechanism by which the gut microbiota influences cholesterol metabolism. In line with our previous study, we found that Abx-depleted gut microbiota for 10 weeks decreased the serum TC and LDL-c levels, confirming the role of gut microbiota in modulating cholesterol metabolism. However, the hepatic TC level was increased by gut microbiota depletion. Furthermore, RNA-seq analysis results showed that the hepatic genes involved in cholesterol synthesis were up-regulated by gut microbiota depletion, which might be the reason for increased hepatic TC level. Through correlation analysis, we observed strong negative associations between butyrate-producing bacteria and hepatic cholesterol level. Additionally, specific elimination of butyrate-producers via metronidazole decreased the colonic butyrate level to an undetectable level and up-regulated the expression of sterol regulatory element-binding protein (Srebp2) and its downstream genes involved in cholesterol biosynthesis in the liver. However, butyrate treatment increased colonic butyrate level and down-regulated the expression of genes associated with cholesterol biosynthesis. Furthermore, a treatment with an antagonist of PPARγ, GW9662, successfully neutralized the suppressed effects of butyrate on the expression of genes involved in cholesterol biosynthesis. Our findings offer insight into how butyrate-producing bacteria play a pivotal role in hepatic cholesterol biosynthesis, supporting the potential of microbiota-based interventions in maintaining cholesterol homeostasis.
Overall, these data suggest that gut microbiota depletion influences hepatic fatty acid and cholesterol metabolism. Moreover, gut microbiota-derived butyrate acts as a molecule that mediates hepatic cholesterol synthesis. Furthermore, PPARγ/SREBP2 signaling was hypothesized to be a mediator between gut microbiota-derived butyrate and hepatic cholesterol synthesis in mice fed an HFD.
