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Lactobacillus rhamnosus B16 Regulates Lipid Metabolism Homeostasis by Producing Acetic Acid

ABSTRACT:

Background Hyperlipidemia, a chronic disorder caused by abnormal lipid metabolism, increases risks of atherosclerosis and cardiovascular diseases.

Current single-target drugs have limited efficacy and side effects, prompting interest in probiotics like Lactobacillus rhamnosus, though their mechanisms remain unclear.Methods A novel Lactobacillus rhamnosus strain from healthy human feces was identified via API 50CH and ANI analysis. Genomic/proteomic analyses characterized metabolic pathways. In vitro assays evaluated cholesterol degradation, gastrointestinal tolerance, and biofilm formation. Foam cell models and Western blotting assessed lipid-related proteins. A high fat diet (HFD)-induced hyperlipidemic mouse model was used for in vivo validation, with serum lipid profiling, histology, and immunohistochemistry. Metabolomic and SCFA analyses identified key metabolites, validated by sodium acetate treatment.

Results We identified a novel strain of Lactobacillus rhamnosus B16 (L. rB16) from healthy human feces, which had cholesterol-lowering ability in a high cholesterol MRS broth. Moreover, we found that heat-inactivated L. rB16 (HI-L. rB16) could reduce foam cell cholesterol levels through the LXRα signaling pathway and regulate hepatic lipid metabolism balance by regulating the expression of key lipid proteins. Metabolomics showed the acetic acid produced by L. rB16 was the main metabolite that exerted the cholesterol-lowering effect.

Conclusions L. rB16 alleviates high-fat-diet-induced hyperlipidemia in mice by reducing cholesterol through acetate-mediated LXRα signaling, demonstrating its therapeutic potential as a probiotic for lipid metabolism disorders.

INSTRUMENT(S): Liquid Chromatography MS - negative - reverse phase, Liquid Chromatography MS - positive - reverse phase

PROVIDER: MTBLS12858 | MetaboLights | 2025-08-14

REPOSITORIES: MetaboLights

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			Action	DRS
	a_MTBLS12858_LC-MS_negative_reverse-phase_metabolite_profiling.txt	Txt
	a_MTBLS12858_LC-MS_positive_reverse-phase_metabolite_profiling.txt	Txt
	i_Investigation.txt	Txt
	m_MTBLS12858_LC-MS_negative_reverse-phase_metabolite_profiling_v2_maf.tsv	Tabular
	m_MTBLS12858_LC-MS_positive_reverse-phase_metabolite_profiling_v2_maf.tsv	Tabular

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Project description:Background and Aims Lipid-lowering therapy is a cornerstone in the treatment of atherosclerotic cardiovascular disease (ASCVD). Although some lipid-lowering drugs have demonstrated positive effects in patients with ASCVD, their effects are limited in those with homozygous familial hypercholesterolemia (HoFH). It is essential to seek new lipid-lowering targets. Yes-associated protein (YAP) may be involved in lipid metabolism in liver; therefore, we investigated the function of hepatocyte YAP in hyperlipidemia and atherosclerosis. Methods Hyperlipidemia models were generated in apoE-/- mice or mice injected with AAV8-D377Y-mPCSK9, which degrades and deletes low density lipoprotein receptor (LDLR), by being fed a high cholesterol diet (HCD) for 12 weeks. We measured the expression level of hepatic YAP in these apoE-/- mice. Next, we created YAPΔHep apoE-/- mice to further determine the role of YAP in hyperlipidemia and atherosclerosis. AML12 cells and mice injected with AAV8-D377Y-mPCSK9 or YAPΔHepapoE-/- mice were used to elucidate its mechanism. Finally, apoE-/- or LDLR-/- mice were used to observe the therapeutic efficacy of AAV8-Alb-shYAP for hyperlipidemia and atherosclerosis. Results HCD-fed apoE-/- mice showed increased levels of YAP in the liver. Further investigation indicated that YAPΔHepapoE-/- mice exhibited lighter hyperlipidemia and atherosclerosis than YAPflox/floxapoE-/- mice fed with HCD. Conversely, hepatocyte-specific overexpression of YAP (5S) deteriorated hyperlipidemia and atherosclerosis in HCD-fed apoE-/- mice. Furthermore, the lipid-lowering effect of YAP deficiency in hepatocytes was independent of LDLR. Hepatocyte-specific overexpression of angiopoietin-like-3 (ANGPTL3) aggravated hyperlipidemia and atherosclerosis in YAPΔHepapoE-/- mice, indicating that ANGPTL3 is responsible for the function of YAP in hyperlipidemia. Mechanistically, YAP upregulated ANGPTL3 via TEAD4 in hepatocytes independent of LDLR. Notably, AAV8-Alb-shYAP lowered lipid levels in apoE-/- or LDLR-/- mice. Conclusion Taken together, our findings revealed a novel role for the YAP-TEAD4-ANGPTL3 axis in lipid metabolism independent of LDLR. Inhibition of hepatocyte YAP may be an effective lipid-lowering strategy for HoFH.

Project description:Preussin (Asperidine B) has recently shown its lipid-lowering effects by inhibiting intestinal absorption in human colorectal adenocarcinoma (Caco-2) cells and ex vivo intestinal loop in rats. While statins are widely prescribed as the primary line drug of choice for lowering hyperlipidemia, ezetimibe is the only drug that reduces intestinal cholesterol absorption, and is also optional for statin-nonresponsive individuals. To gain more understanding of the mechanisms of action and lead compounds, the derivatives of preussin: TP3, TP4, TP5, TP6, and TP7 have recently been synthesized, and the structures were confirmed using 1D and 2D nuclear magnetic resonance (NMR) spectroscopy. However, whether these derivatives exhibited inhibitory effects on cholesterol absorption is unknown. Thus, this study aims to investigate the most potent inhibitory effect of cholesterol absorption of preussin derivatives using fluorescent-micelle cholesterol transport in intestinal Caco-2 cells, confirmed by an in vivo cholesterol absorption assay. Possible targets of the lead compounds were identified using a protein binding assay and label-free quantification using proteomic analyses. Results showed that all tested preussin derivatives markedly inhibited cholesterol absorption in the intestinal Caco2 cells to a similar extent to preussin and ezetimibe. TP5 (preussin B) consistently displayed a significant reduction of plasma cholesterol, identical to preussin and ezetimibe, with the same potency in rats. In addition, the proteomic analysis found that substantial differentially expressed changes in six proteins are involved in the lipid metabolism pathway. Interestingly, GOT2, as one of these six proteins in the lipid transport pathway, consistently interacts with TP5. The molecular docking and dynamic prediction showed that TP5 coupled with GOT2 at a pocket comparable to its cofactor. These findings suggest that preussin B has therapeutic potential as a candidate for a cholesterol absorption inhibitor to treat hyperlipidemia.

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Lactobacillus rhamnosus B16 Regulates Lipid Metabolism Homeostasis by Producing Acetic Acid

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