Project description:Background & Aims Obesity is a major risk factor for metabolic associated steatotic liver disease (MASLD) which can progress from metabolic associated steatotic liver (MASL) to metabolic associated steatohepatitis (MASH). There are currently no effective and validated screening tools to stratify obese patients with a greater risk for MASH, independent of liver fibrosis, at a population level. We aimed to characterise the highly abundant and small protein plasma proteomes of worsening MASLD and overlay the liver-secreted proteome to generate a predictive model to stratify patients with and without MASH. Methods Venous blood and liver wedge biopsies were taken from 160 patients undergoing bariatric surgery. MASLD severity was assessed histologically. Liver biopsies from a subset of 96 patients were precision-cut and cultured to assess liver-secreted proteins. Proteomic analysis was performed using liquid chromatography-tandem mass spectrometry on the plasma and the incubation medium cutoff the liver slices. Results Current non-invasive scores failed to stratify MASH in our cohort. The top200 plasma proteome exhibited mild changes in patients with MASH compared to those with No pathology, while the SPEA approach identified substantial differences in plasma proteins of patients with MASH compared to those without MASH. Liver-secreted proteins were remodelled in MASH compared to MASL and individuals with No pathology. There were no significant changes in the liver-secreted proteins and plasma proteome when comparing MASL to those with No pathology. The APASHA model, comprised of APOF, PCSK9, AFM, and S100A6, HbA1c % and AZGP1 stratified MASH in the discovery (AUROC: 0.887, p<0.0001) and validation cohorts (AUROC:0.7673, p=0.0002) and outcompeted other non-invasive scores. Conclusions These proteomic investigations provide a detailed description of liver-secreted and plasma proteome with worsening MASLD. MASH remodels plasma and liver-secreted proteins. Plasma proteomics generated the APASHA model validated in two Australian bariatric cohorts. Further investigation is warranted to interrogate the utility of the APASHA model as a non-invasive risk prediction model in additional cohorts. Lay Summary: Metabolic-associated steatohepatitis (MASH), a more advanced form of metabolic-associated steatotic liver disease (MASLD), alters the levels of many proteins secreted by the liver and in the blood and those. The APASHA model, which is based on proteins that change in the blood or are secreted by the liver in cases of MASH, could potentially be developed into a simple blood test to predict MASH in high-risk groups.

Project description:Background & Aims Obesity is a major risk factor for metabolic associated steatotic liver disease (MASLD) which can progress from metabolic associated steatotic liver (MASL) to metabolic associated steatohepatitis (MASH). There are currently no effective and validated screening tools to stratify obese patients with a greater risk for MASH, independent of liver fibrosis, at a population level. We aimed to characterise the highly abundant and small protein plasma proteomes of worsening MASLD and overlay the liver-secreted proteome to generate a predictive model to stratify patients with and without MASH. Methods Venous blood and liver wedge biopsies were taken from 160 patients undergoing bariatric surgery. MASLD severity was assessed histologically. Liver biopsies from a subset of 96 patients were precision-cut and cultured to assess liver-secreted proteins. Proteomic analysis was performed using liquid chromatography-tandem mass spectrometry on the plasma and the incubation medium cutoff the liver slices. Results Current non-invasive scores failed to stratify MASH in our cohort. The top200 plasma proteome exhibited mild changes in patients with MASH compared to those with No pathology, while the SPEA approach identified substantial differences in plasma proteins of patients with MASH compared to those without MASH. Liver-secreted proteins were remodelled in MASH compared to MASL and individuals with No pathology. There were no significant changes in the liver-secreted proteins and plasma proteome when comparing MASL to those with No pathology. The APASHA model, comprised of APOF, PCSK9, AFM, and S100A6, HbA1c % and AZGP1 stratified MASH in the discovery (AUROC: 0.887, p<0.0001) and validation cohorts (AUROC:0.7673, p=0.0002) and outcompeted other non-invasive scores. Conclusions These proteomic investigations provide a detailed description of liver-secreted and plasma proteome with worsening MASLD. MASH remodels plasma and liver-secreted proteins. Plasma proteomics generated the APASHA model validated in two Australian bariatric cohorts. Further investigation is warranted to interrogate the utility of the APASHA model as a non-invasive risk prediction model in additional cohorts.

Project description:Why age is the primary driver of the most common dementia-Alzheimer’s disease (AD)? Autophagy plays fundamental roles in cellular homeostasis, metabolic energetics, and in maintaining cellular resilience such as via eliminating damaged mitochondria. It is proposed that impaired autophagy leads to compromised catabolic degradation of amyloid beta (Aβ) and Tau pathologies, the disease-defining pathologies of AD; however, molecular mechanisms on whether and if yes, why reduced autophagy during ageing and its contribution to AD, especially in human samples, are largely elusive. By using serum and CSF samples from a healthy ageing cohort (n = 22 with 4-year follow up samples) and an AD cohort (n = 391), we show that the abundance of ULK1 protein in serum and CSF decreases with increasing age and is extremely lower in AD patients than in age-matched controls. In a large number of postmortem human brain samples (n = 72), expression of ULK1 in entorhinal cortical and hippocampal neurons in AD patients is significantly lower than in neurons from cognitive normal controls. To investigate whether ULK1 reduction is a bystander or cause/risk of AD, we generated a ubiquitously ULK1-ov mouse model and an AAV-based CA1 neuronal ULK1-ov mouse model in Aβ-bearing background; ULK1 overexpression stimulates autophagic and phagocytic degradation of Aβ, improves mitochondrial quality, thereby delaying progressive cognitive loss. Similarly, in hTau.P301S mice, overexpression of ULK1 inhibits Tau pathology and inhibits memory loss; mechanistically, ULK1 upregulation increases autophagy which increases cellular NAD+, leading to the inhibition of acetylated Tau174 (a cause of Tau pathology) through the NAD+/SIRT1 axis. ULK1 is likely a druggable target for AD as small molecule activators of ULK1 antagonize AD progression which is dependent on PINK1- and FUNDC1-related mitophagy. We propose age-dependent autophagy impairment risks AD due to ULK1 reduction, opening a new window for anti-AD therapeutics.

			Action	DRS
	20250617_104146_SS21_RSI1_AB.sne	Other
	20250617_151939_SS21_RS1_Ph.sne	Other
	FeatureLevelData_AB.txt	Txt
	FeatureLevelData_PH.txt	Txt
	GroupComparisonsData_AB.txt	Txt

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The ULK1-NCOA3 axis restrains de novo lipogenesis and prevents progression of MASLD

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