Sphingosine kinase 2 (SphK2) knockout increases liver inflammation in an early MASH mouse model
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE280083 | GEO | 2024/11/20
REPOSITORIES: GEO
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Project description:To determine the effect of SphK2 KO on liver metabolic-associated gene expression in an early MASH mouse model To determine the effect of WDSW on liver metabolic-associated gene expression in an early MASH mouse model
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Project description:Sphingosine kinase 2 (SphK2) knockout increases liver inflammation in an early MASH mouse model
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Project description:Sphingosine kinase 2 (SphK2) knockout alters metabolic gene expression in an early MASH mouse model
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Project description:While macrophage heterogeneity during Metabolic dysfunction-associated steatohepatitis (MASH) has been described, the fate of these macrophages during MASH regression is poorly understood. Comparing macrophage heterogeneity during MASH progression vs regression, we identified specific macrophage sub- populations that are critical for MASH/fibrosis resolution. We elucidated the restorative pathways and gene signatures that define regression associated macrophages (RAM) and establish the importance of TREM2+ macrophages during MASH regression. Liver resident Kupffer cells are lost during MASH and are replaced by four distinct monocyte derived macrophage sub-populations. Trem2 is expressed in two macrophage sub- populations: (i) monocyte-derived macrophages occupying the Kupffer cell niche (MoKC) and (ii) lipid-associated macrophages (LAM). In regression livers, no new transcriptionally distinct MF sub-population emerged. However, the relative macrophage composition changed during regression compared to MASH. While MoKC was the major macrophage sub-population during MASH, they decreased during regression. LAM was the dominant macrophage sub-type during MASH regression and maintained Trem2 expression. Both MoKC and LAM were enriched in disease resolving pathways. Absence of TREM2 restricted the emergence of LAMs and formation of hepatic crown like structures (hCLS). TREM2+ macrophages are functionally important not only for restricting MASH-fibrosis progression, but also for effective regression of inflammation and fibrosis. TREM2+ MF are superior collagen degraders. Lack of TREM2+ macrophages also prevented elimination of hepatic steatosis and inactivation of HSC during regression, indicating their significance in metabolic co-ordination with other cell- types in the liver. TREM2 imparts this protective effect through multifactorial mechanisms, including improved phagocytosis, lipid-handling and collagen degradation.
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Project description:Non-alcoholic steatohepatitis (NASH) represents a significant and growing public health concern worldwide, characterized by hepatic steatosis, inflammation, and varying degrees of fibrosis. In vitro models of NASH play a crucial role in elucidating the underlying mechanisms of disease pathogenesis, identifying potential therapeutic targets, and evaluating the efficacy of pharmacological interventions. Several preclinical models of MASH have been developed and are being used extensively to study these areas. While standard cell culture models allow for elucidation of certain molecular pathways involved in MASH pathogenesis, they lack three-dimensional architecture and cellular heterogeneity observed in native liver tissue, potentially limiting their physiological relevance and inability to fully capture the multifactorial nature of the disease Precision cut liver slices from MASH livers retain the complex multicellular architecture of the liver including hepatocyte arrangement, sinusoidal structure, and cellular interactions, but the metabolism deteriorates over a short period of time (usually reported as 2 days). Human liver organoids from iPSCs (induced pluripotent stem cells) retain the genetics of the patients but fail to fully differentiate into hepatocytes or have the liver architecture. Human liver spheroids incubated in a MASH cocktail develop several phenotypic characteristics of a MASH liver, but the small spheroid size precludes extensive histological comparisons to MASH livers. Microphysiological systems (MPS) or “liver on a chip” in which 3D cultures are perfused, maintain many of the physiological functions of the liver owing to precise control over microenvironmental parameters, including fluid flow, nutrient gradients, and mechanical cues. However, MPS are difficult to scale up and have not been developed to reproduce a MASH phenotype. In comparison, bioprinted liver tissues for MASH have many advantages. Organovo’s 3D bioprinted liver tissues are comprised of all major primary liver cells including hepatocytes, endothelial cells, stellates and Kupffer cells, mixed in physiologically relevant ratios. These cells are then bioprinted in precise pre-defined liver specific geometries to recapitulate complexity of the hepatic microenvironment.. This mimicking of tissue architecture enables more accurate representation of cellular interactions, spatial organization, and microenvironmental cues crucial for MASH pathogenesis. The liver tissues developed using this method maintain differentiation and metabolism over several weeks. In this paper, we further demonstrated that upon treatment with a MASH induction cocktail, these liver tissues respond accurately by developing steatosis and fibrosis Tissue response varies depending in response to the complexity of the MASH cocktail.
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Project description:Metabolic dysfunction-associated steatohepatitis (MASH) is a chronic liver disease associated with hepatic inflammation and fibrosis. Inflammasome-mediated IL-18 signaling is enhanced under MASH condition. IL-18 binding protein (IL-18BP) is a soluble protein that can block IL-18 actions and therapeutic potential of IL-18BP for MASH-induced fibrosis is largely unknown. We newly developed a human IL-18BP biologics (APB-R3) and injected it to mice to evaluate its pharmacologic efficacy. APB-R3 strikingly abolished hepatic fibrosis and reduced collagen markers. We further investigated whether APB-R3 could inhibit fibrotic activation of hepatic stellate cells (HSCs). This study proposes that abrogation of IL-18 signaling by boosting IL-18BP can strongly inhibit the development of MASH-induced fibrosis and our engineered IL-18BP biologics can become promising therapeutic candidate for curing MASH.
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Project description:Metabolic-associated steatohepatitis (MASH), the inflammatory stage of MASLD, will soon be one of the primary causes of liver-related complications, including advanced fibrosis and hepatocellular carcinoma. Its steady increase in both the US and the global population is devastating. Between the two genders, more women are suffering from MASH compared to the man due to estrogen deficiency caused by polycystic ovary syndrome or menopause. Our published data shows a clear positive association between the progression of liver disease and the expression of novel hexokinase HKDC1 in the liver. Targeting HKDC1, which is highly expressed in pathological hepatocytes (in MASH) but negligible in normal hepatocytes, represents a highly selective approach. Therefore, we hypothesized that liver-specific deletion of HKDC1 will protect against diet-induced obesity and the progression of MASH to fibrosis. We used an early-onset liver knockout (LKO) of HKDC1 by crossing HKDC1 floxed mice with Albumin Cre mice to test our hypothesis. We fed the Western Diet to HKDC1LKO female mice along with HKDC1 floxed mice (HKDC1fl/fl; as Controls) for 28 weeks. Our data shows that HKDC1 deletion significantly decreases body weight and fat mass compared to HKDC1fl/fl mice with no changes in food intake and energy expenditure. Knockout mice have better glucose tolerance and lower fasting glucose levels than HKDC1fl/fl mice. Our data also shows that the knockout group has smaller livers, healthier liver parameters, less steatosis, and lower NAS and fibrosis scores. Furthermore, HKDC1 knockout alters hepatic gene expression, and we found significantly low proinflammatory and profibrogenic gene expression in the LKO mice. Although we did not see any changes in triglyceride levels, there was a significant reduction of serum cholesterol concomitant with enhanced expression of cholesterol metabolism genes in the knockout group. Our data suggest a promising protective role of HKDC1 deletion against diet-induced obesity and MASH mice.
2024-11-27 | GSE283058 | GEO
Project description:Recent findings reveal the importance of tryptophan-initiated de novo nicotinamide adenine dinucleotide (NAD+) synthesis in the liver, a process previously considered secondary to biosynthesis from nicotinamide. Here we show that inhibiting α-amino-β-carboxymuconate-ε-semialdehyde decarboxylase (ACMSD) promotes de novo NAD+ synthesis and reduces DNA damage ex vivo, in vivo and in human liver organoid (HLO) models. In mouse models of MASLD/MASH, de novo NAD+ biosynthesis is suppressed, and transcriptomic DNA damage signatures correlate with disease severity; In humans, Mendelian randomization-based genetic analysis suggests a notable impact of genomic stress on liver disease susceptibility. Therapeutic inhibiting ACMSD in mice elevates liver NAD+ and reverses MASLD/MASH, mitigating fibrosis, inflammation and DNA damage. Similar outcomes are recapitulated in HLO models of steatohepatitis and DNA damage. Our findings highlight the benefits of ACMSD inhibition for boosting hepatic NAD+ and genomic protection, indicating its therapeutic promise in liver diseases marked by NAD+ and genomic stress.
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Project description:Recent findings reveal the importance of tryptophan-initiated de novo nicotinamide adenine dinucleotide (NAD+) synthesis in the liver, a process previously considered secondary to biosynthesis from nicotinamide. Here we show that inhibiting α-amino-β-carboxymuconate-ε-semialdehyde decarboxylase (ACMSD) promotes de novo NAD+ synthesis and reduces DNA damage ex vivo, in vivo and in human liver organoid (HLO) models. In mouse models of MASLD/MASH, de novo NAD+ biosynthesis is suppressed, and transcriptomic DNA damage signatures correlate with disease severity; In humans, Mendelian randomization-based genetic analysis suggests a notable impact of genomic stress on liver disease susceptibility. Therapeutic inhibiting ACMSD in mice elevates liver NAD+ and reverses MASLD/MASH, mitigating fibrosis, inflammation and DNA damage. Similar outcomes are recapitulated in HLO models of steatohepatitis and DNA damage. Our findings highlight the benefits of ACMSD inhibition for boosting hepatic NAD+ and genomic protection, indicating its therapeutic promise in liver diseases marked by NAD+ and genomic stress.
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