Induction of autophagy via the PI3K/Akt/mTOR signaling pathway by Pueraria flavonoids improves non-alcoholic fatty liver disease in obese mice.

The liver immune microenvironment is a key element in the development of hepatic inflammation in NAFLD. ApoA4 deficiency increases the hepatic lipid burden, insulin resistance, and metabolic inflammation. However, the effect of ApoA4 on liver immune cells and the precise immune cell subsets that exacerbate fatty liver remain elusive. The aim of this study was to profile the hepatic immune cells affected by ApoA4 in NAFL. We performed scRNA-seq on liver immune cells from WT and ApoA4-deficient mice administered a high-fat diet. Immunostaining and qRT–PCR analysis were used to validate the results of scRNA-seq. We identified 10 discrete immune cell populations comprising macrophages, DCs, granulocytes, B, T and NK&NKT cells and characterized their subsets, gene expression profiles, and functional modules. ApoA4 deficiency led to significant increases in the abundance of specific subsets, including inflammatory macrophages (2-Mφ-Cxcl9 and 4-Mφ-Cxcl2) and activated granulocytes (0-Gran-Wfdc17). Moreover, ApoA4 deficiency resulted in higher Lgals3, Ctss, Fcgr2b, Spp1, Cxcl2, and Elane levels and lower Nr4a1 levels in hepatic immune cells. These genes were consistent with human NAFLD-associated marker genes linked to disease severity. The expression of NE and IL-1β in granulocytes and macrophages as key ApoA4 targets were validate in the presence or absence of ApoA4 by immunostaining. The scRNA-seq data analyses revealed reprogramming of liver immune cells resulted from ApoA4 deficiency. We uncovered that the emergence of ApoA4-associated immune subsets (namely Cxcl9+ macrophage, Cxcl2+ macrophage and Wfdc17+ granulocyte), pathways, and NAFLD-related marker genes may promote the development of NAFL. These findings may provide novel therapeutic targets for NAFL and the foundations for further studying the effects of ApoA4 on immune cells in various diseases.

/pdf/single-cell-rna-sequencing-reveals-a-novel-inhibitory-effect-3i4o7tip.pdf

Single-cell RNA sequencing reveals a novel inhibitory effect of ApoA4 on NAFL mediated by liver-specific subsets of myeloid cells

ABSTRACT Diet-induced metabolic dysfunction-associated steatotic liver disease (MASLD) is a prevalent metabolic disorder with limited effective interventions available. A novel approach to address this issue is through gut microbiota-based therapy. In our study, we utilized multi-omics analysis to identify Phocaeicola vulgatus (P. vulgatus) as a potential probiotic for the treatment of MASLD. Our findings from murine models clearly illustrate that the supplementation of P. vulgatus mitigates the development of MASLD. This beneficial effect is partly attributed to the metabolite 3-Hydroxyphenylacetic acid (3-HPAA) produced by P. vulgatus, which reduces the acetylation levels of H3K27 and downregulates the transcription of Squalene Epoxidase (SQLE), a rate-limiting enzyme in steroid biosynthesis that promotes lipid accumulation in liver cells. This study underscores the significant role of P. vulgatus in the development of MASLD and the critical importance of its metabolite 3-HPAA in regulating lipid homeostasis. These findings offer a promising avenue for early intervention therapy in the context of MASLD.

Phocaeicola vulgatus alleviates diet-induced metabolic dysfunction-associated steatotic liver disease progression by downregulating histone acetylation level via 3-HPAA

Significance of CCNs in liver regeneration

Alternative pathway of bile acid biosynthesis contributes to ameliorate NASH after induction of NAMPT/NAD+/SIRT1 axis.

SCOPE
Hepatic steatosis and insulin resistance (IR) are risk factors for many metabolic syndromes such as NAFLD and T2DM. ApoA4 improves glucose hemostasis by increasing glucose-stimulated insulin secretion and glucose uptake via PI3K-Akt activation in adipocytes. However, whether ApoA4 has an effect on hepatic steatosis or IR remains unclear.


METHODS AND RESULTS
ApoA4-knockout (KO) aggravates diet-induced obesity, hepatic steatosis and IR in mice promoted by increased hepatic lipogenesis gene expression based on RNA-seq data. Conversely, liver-specific overexpression of ApoA4 via AAV-ApoA4 transduction reverses the effect in ApoA4-KO mice, accompanied by suppressed hepatic lipogenesis, increased lipolysis, and fatty acid oxidation. Short-term treatment with recombinant ApoA4 protein improves glucose clearance and liver insulin sensitivity, and reduces hepatic lipogenesis gene expression in the absence of insulin. Moreover, in primary hepatocytes and a hepatic cell line, ApoA4 improves hepatic glucose uptake via IRS-PI3K-Akt signaling and decreases fat deposition and hepatic lipogenesis gene expression by inhibiting SREBF1 activity.


CONCLUSION
ApoA4 restricts hepatic steatosis by inhibiting SREBF1-mediated lipogenesis and improves insulin sensitivity and glucose uptake via IRS-PI3K-Akt signaling in the liver. These findings indicate that ApoA4 may serve as a therapeutic target for obesity-associated NAFLD. This article is protected by copyright. All rights reserved.

Apolipoprotein A4 Restricts Diet-induced Hepatic Steatosis via SREBF1-mediated Lipogenesis and Enhances IRS-PI3K-Akt Signaling.

NADH:ubiquinone oxidoreductase core subunit S8 (NDUFS8) is an essential core subunit and component of the iron-sulfur (FeS) fragment of mitochondrial complex I directly involved in the electron transfer process and energy metabolism. Pathogenic variants of the NDUFS8 are relevant to infantile-onset and severe diseases, including Leigh syndrome, cancer, and diabetes mellitus. With over 1000 nuclear genes potentially causing a mitochondrial disorder, the current diagnostic approach requires targeted molecular analysis, guided by a combination of clinical and biochemical features. Currently, there are only several studies on pathogenic variants of the NDUFS8 in Leigh syndrome, and a lack of literature on its precise mechanism in cancer and diabetes mellitus exists. Therefore, NDUFS8-related diseases should be extensively explored and precisely diagnosed at the molecular level with the application of next-generation sequencing technologies. A more distinct comprehension will be needed to shed light on NDUFS8 and its related diseases for further research. In this review, a comprehensive summary of the current knowledge about NDUFS8 structural function, its pathogenic mutations in Leigh syndrome, as well as its underlying roles in cancer and diabetes mellitus is provided, offering potential pathogenesis, progress, and therapeutic target of different diseases. We also put forward some problems and solutions for the following investigations.

/pdf/emerging-roles-of-ndufs8-located-in-mitochondrial-complex-i-30tkm4y9.pdf

Emerging Roles of NDUFS8 Located in Mitochondrial Complex I in Different Diseases

CCN6 is a secretory protein with functions of maintaining mitochondrial homeostasis and anti‐oxidative stress; and yet, whether it is involved in the pathogenesis of non‐alcoholic steatohepatitis (NASH) is still obscure. We investigated the role and mechanism of CCN6 in the development of NASH.

CCN6 improves hepatic steatosis, inflammation, and fibrosis in non‐alcoholic steatohepatitis

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Apolipoprotein A4 Restricts Diet-induced Hepatic Steatosis via SREBF1-mediated Lipogenesis and Enhances IRS-PI3K-Akt Signaling.

Emerging Roles of NDUFS8 Located in Mitochondrial Complex I in Different Diseases

CCN6 improves hepatic steatosis, inflammation, and fibrosis in non‐alcoholic steatohepatitis