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I3A Improves the Hepatic Mitochondrial Respiration Defects in NAFLD Disease Model

ABSTRACT: Recent evidences have linked indole-3-acetic acid (I3A), a gut microbiota-derived metabolite from dietary tryptophan, with the resistance to liver diseases. However, data supporting I3A-mediated protection against nonalcoholic fatty liver disease (NAFLD) remain incomprehensive. In this study, we verified that I3A definitely alleviates dietary-induced metabolic impairments, particularly glucose dysmetabolism and liver steatosis. Importantly, we expand the understanding of I3A further to enhancing mitochondrial respiration complex (MRC) capacity by RNA-seq. We found that I3A restored the deficiency of MRC capacity in palmitic acid (PA)-induced HepG2 in vitro. These changes were associated with complex I and III expression and their activities. In addition, pre-treatment of I3A guard against the deficiency of not only the MRC capacity but also ATP production due to the advanced protection effect on the expression and activity of complex V. In conclusion, our findings uncover that I3A increased expression and activity of hepatic oxidative phosphorylation subunits, contributing to mitochondrial respiration improvement in NAFLD mice.

ORGANISM(S): Mus musculus

PROVIDER: GSE180353 | GEO | 2022/11/17

REPOSITORIES: GEO

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Mtfp1 ablation enhances mitochondrial respiration and protects against hepatic steatosis- Co-IP

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2023-11-27 | PXD046262 | Pride

Mtfp1 ablation enhances respiration and protects against hepatic steatosis

Project description:Hepatic steatosis is the result of an imbalance between nutrient delivery and metabolism in the liver. It is the first hallmark of Non-alcoholic fatty liver disease (NAFLD) and is characterized by the accumulation of excess lipids in the liver that can drive liver failure, inflammation, and cancer. Mitochondria control the fate and function of cells and compelling evidence implicates these multifunctional organelles in the appearance and progression of liver dysfunction, although it remains to be elucidated which specific mitochondrial functions are actually causally linked to NAFLD. In this study, we identified Mitochondrial Fission Process 1 protein (MTFP1) as a key regulator of mitochondrial and metabolic activity in the liver. Deletion of Mtfp1 in hepatocytes is physiologically benign in mice yet leads to the upregulation of oxidative phosphorylation (OXPHOS) complexes and mitochondrial respiration, independently of mitochondrial biogenesis. Consequently, hepatocyte-specific knockout mice are protected against high fat diet-induced hepatic steatosis and metabolic dysregulation. Additionally, we find that deletion of Mtfp1 in liver mitochondria inhibits mitochondrial permeability transition pore opening in hepatocytes, conferring protection against apoptotic liver damage in vivo and ex vivo. Our work uncovers novel functions of MTFP1 in the liver, positioning this gene as an unexpected regulator of OXPHOS and a therapeutic candidate for NAFLD.

2023-11-27 | PXD041197 | Pride

Fibroblast growth factor 21 reflects liver fat accumulation and dysregulation of signalling pathways in the liver of C57BL/6J mice

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2016-08-09 | E-GEOD-84495 | biostudies-arrayexpress

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Project description:With the improvement of people's living standards and lifestyle changes, nonalcoholic fatty liver disease (NAFLD) has become one of the most common chronic liver diseases worldwide. However, few drugs are available for NAFLD, partly due to an incomplete understanding of its pathogenic mechanisms. Here, using in vivo and in vitro gain- and loss-of function approaches, we identified DKK1 as a pivotal mediator of the progression of NAFLD and its accompanying metabolic disorders in dietary obese mice. Mechanistic study reveals that DKK1 enhances the capacity of hepatocytes to uptake fatty acids through ERK-PPARγ-CD36 pathway. Moreover, DKK1 increased insulin resistance by activating the JNK signaling pathway, which in turn exacerbates disorders of hepatic lipid metabolism. These results suggest that DKK1 is a regulator of fatty acid uptake in lipid metabolism and insulin signaling, and may be a potential therapeutic candidate for NAFLD

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Project description:The pathogenesis of non-alcoholic fatty liver disease (NAFLD) is associated with abnormalities of liver lipid metabolism, especially with the accumulation of saturated fatty acids (FA). On the contrary, a diet enriched with n-3 polyunsaturated FA (n-3-PUFA) has been reported to ameliorate the progression of NAFLD. The aim of our study was to investigate the impact of dietary n-3-PUFA enrichment on the development of NAFLD and liver lipidome. Mice were fed for 6 weeks either high-fat methionine choline-deficient diet (MCD) or standard chow (two groups fed MCD, two control groups, both with or without n-3-PUFA). Genome-wide transcriptome analysis of liver tissue was performed and revealed differences in liver mRNA transcriptomes after MCD as well as n-3-PUFA administration.

2023-12-14 | E-MTAB-13399 | biostudies-arrayexpress

Hepatocyte RNA-seq analysis in liver-specific XBP1 knockout mice fed a high fat sugar diet

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2022-01-03 | GSE190947 | GEO

Bilophila wadsworthia worsens high-fat diet-induced metabolic impairments in inflammation dependent and independent manners [bacterial gene expression]

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Bilophila wadsworthia worsens high-fat diet-induced metabolic impairments in inflammation dependent and independent manners [mouse gene expression]

2018-05-26 | GSE111451 | GEO

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Project description:Non-alcoholic fatty liver disease (NAFLD) is a sexually dimorphic disease influenced by dietary factors. Here, we assess the metabolic and hepatic effects of dietary amino acid (AA) source in Western diet (WD)-induced NAFLD in male and female mice. The AA source was either casein or a free AA mixture mimicking the composition of casein. As expected, males fed a casein-based WD displayed glucose intolerance, fasting hyperglycemia, and insulin-resistance and developed NAFLD associated with changes in hepatic gene expression and dysbiosis. In contrast, males fed the AA-based WD showed no steatosis, a similar gene expression profile as males fed a control diet, and a distinct microbiota composition compared to males fed a casein-based WD. Females were protected against WD-induced liver damage, hepatic gene expression, and gut microbiota changes regardless of the AA source. Thus, free dietary AA intake prevents the unhealthy metabolic outcomes of a WD in a sex-specific manner.

2024-01-01 | GSE234591 | GEO

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Project description:Objective: Bone marrow-derived myeloid cells accumulate in the liver as monocytes and macrophages during the progression of obesity-related non-alcoholic fatty liver disease (NAFLD) to steatohepatitis (NASH). Myeloid cells comprise heterogeneous subsets, and dietary overnutrition may affect macrophages in liver and bone marrow. We therefore aimed at characterizing in-depth the functional adaptations of myeloid cells in fatty liver. Design: We employed single-cell RNA-sequencing to comprehensively assess the heterogeneity of myeloid cells in liver and bone marrow during NAFLD, by analyzing C57BL/6 mice fed with a high-fat, high-sugar, high-cholesterol "Western diet" for 16 weeks. We also characterized NAFLD-driven functional adaptations of macrophages in vitro and their functional relevance during steatohepatitis in vivo.

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