Dysregulated hepatic lipid metabolism and gut microbiota associated with early-stage NAFLD in ASPP2-deficiency mice

Abstract

BackgroundGrowing evidence indicates that lipid metabolism disorders and gut microbiota dysbiosis were related to the progression of non-alcoholic fatty liver disease (NAFLD). Apoptosis-stimulating p53 protein 2 (ASPP2) has been reported to protect against hepatocyte injury by regulating the lipid metabolism, but the mechanisms remain largely unknown. In this study, we investigate the effect of ASPP2 deficiency on NAFLD, lipid metabolism and gut microbiota using ASPP2 globally heterozygous knockout (ASPP2+/-) mice.MethodsASPP2+/- Balb/c mice were fed with methionine and choline deficient diet for 3, 10 and 40 day to induce an early and later-stage of NAFLD, respectively. Fresh fecal samples were collected and followed by 16S rRNA sequencing. HPLC-MRM relative quantification analysis was used to identify changes in hepatic lipid profiles. The expression level of innate immunity-, lipid metabolism- and intestinal permeability-related genes were determined. A spearman’s rank correlation analysis was performed to identify possible correlation between hepatic medium and long-chain fatty acid and gut microbiota in ASPP2-deficiency mice.ResultsCompared with the WT control, ASPP2-deficiency mice developed moderate steatosis at day 10 and severe steatosis at day 40. The levels of hepatic long chain omega-3 fatty acid, eicosapentaenoic (EPA, 20:5 n-3) and docosahexaenoic (DHA, 22:6 n-3), were decreased at day 10 and increased at day 40 in ASPP+/- mice. Fecal microbiota analysis showed significantly increased alpha and beta diversity, as well as the composition of gut microbiota at the phylum, class, order, family, genus, species levels in ASPP2+/- mice. Moreover, ASPP-deficiency mice exhibited impaired intestinal barrier function, reduced expression of genes associated with chemical barrier (REG3B, REG3G, Lysozyme and IAP), and increased expression of innate immune components (TLR4 and TLR2). Furthermore, correlation analysis between gut microbiota and fatty acids revealed that EPA was significantly negatively correlated with Bifidobacterium family.ConclusionOur findings suggested that ASPP2-deficiency promotes the progression of NAFLD, alterations in fatty acid metabolism and gut microbiota dysbiosis. The long chain fatty acid EPA was significantly negatively correlated with Bifidobacterial abundance, which is a specific feature of NAFLD in ASPP2-deficiency mice. Totally, the results provide evidence for a mechanism of ASPP2 on dysregulation of fatty acid metabolism and gut microbiota dysbiosis.

Low intake of ruminant trans fatty acids ameliorates the disordered lipid metabolism in C57BL/6J mice fed a high-fat diet

“…34,35 However, the dysregulation of lipid metabolism often associated with health problems, for example, the disordered lipid metabolism, is an adverse factor for the development of CVD and NAFLD. [36][37][38] Our current research suggested that a low dosage of R-TFA improved the disordered lipid metabolism in the C57BL/6J mice fed a high-fat diet, and lipidomics analysis revealed that it rehabilitated the hepatic levels of 2 TGs, 3 PEs, 1 PC, 1 FA and 1 Cer, exhibiting a salutary effect. The arachidonic acid metabolic pathway links lipid metabolism with inflammation and plays a crucial role in the occurrence and progression of metabolism-related diseases (e.g., obesity, NAFLD and CVD).…”

Updated mechanisms of MASLD pathogenesis

“…Gut microbes (GM) play a pivotal role in metabolic homeostasis, and disruptions in gut microbial homeostasis can lead to the development of a variety of metabolic disorders, including MASLD [ 107 , 108 ]. Dysbiosis of the intestinal flora may increase the permeability of the intestinal barrier, which leads to enhanced absorption of fatty acids [ 109 ]. On the other hand, intestinal damage may induce liver damage by exposing the liver to bacteria and their products, such as endotoxins [ 110 ].…”

Mechanisms and Therapeutic Strategies for MAFLD Targeting TLR4 Signaling Pathways

“…Altered gut microbial composition could increase pro-inflammatory factors like TNF-α and IL-6 by activating TLR4 signaling pathways [ 40 ]. In animal models, alterations in gut microbiota composition and barrier function by apoptosis-stimulating p53 protein 2 (ASPP2) global heterozygous gene knockout, along with upregulation of TLR4, have been observed in the progression of NAFLD [ 41 ]. Similarly, HFD can significantly increase the expression of TNF-α, TLR-2, TLR-4, IL-6, and NF-κB in the liver and ileum by altering the composition of the gut microbiota and the relative abundance of some intestinal flora to promote steatosis [ 42 ].…”