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Cyclo(His-Pro): A further step in the management of steatohepatitis

ABSTRACT: Non-alcoholic fatty liver disease (NAFLD) is now considered the most common liver disease in the world, yet no pharmacological treatment has been approved. The naturally occurring compound Cyclo (His-Pro) (CHP) appears as an interesting candidate for the management of NAFLD, given its safety records and its anti-inflammatory effect. We show here that CHP administration protects against progression towards steatohepatitis (NASH) and fibrosis in two different mouse models of liver injury: a model of dietary NAFLD/NASH, achieved with thermoneutral housing in combination with a western diet, and a model of liver fibrosis by repeated injections with carbon tetrachloride. CHP administration prevents overall lipid accumulation, reducing body weight and fat mass. Treated animals show lower systemic inflammation and improved glycemia. Histo-pathology and liver transcriptomics highlight reduced steatosis upon CHP, together with lower inflammation and fibrosis, which are typical features of NAFLD progression. For the first time, we identified ERK as an early mediator of CHP response, although more work is required to elucidate its precise mechanism of action. In conclusion, our work indicates that CHP is a novel and efficacious strategy to manage NAFLD, fuelling optimism for potential clinical studies.

ORGANISM(S): Mus musculus

PROVIDER: GSE216366 | GEO | 2023/08/14

REPOSITORIES: GEO

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Cyclo(His-Pro): A further step in the management of steatohepatitis

Project description:Non-alcoholic fatty liver disease (NAFLD) is now considered to be the most common liver disease in the world, and despite this has no approved therapy. The naturally occurring compound Cyclo (His-Pro) (CHP) has been described as having anti-inflammatory and hypoglycemic properties. We show that CHP administration in a mouse model of NAFLD/NASH protects against disease progression. Based on our study, CHP prevents overall lipid accumulation, reducing body weight and fat mass. The treatment lowers systemic inflammation and prevents the development of insulin resistance. Specifically, the effect of CHP in the liver is remarkable, it reduces the steatosis while preventing inflammation and fibrosis, typical features of NADLF/NASH progression. The analysis of the liver transcriptome underscores the anti-fibrotic and anti-inflammatory effects of the treatment, supported by histology results. CHP, which has an excellent safety record, may hence represent a novel approach to manage NAFLD.

2023-08-14 | GSE200750 | GEO

Cyclo (His-Pro): a further step in the prevention of steatohepatitis

2023-08-14 | GSE230745 | GEO

Cyclo His-Pro halts skeletal muscle degeneration and cardiomyopathy in murine myopathy models

Project description:Among the inherited myopathies, a group of muscular disorders characterized by structural and metabolic impairments in skeletal muscle, Duchenne muscular dystrophy (DMD) stands out for its devastating progression. Caused by the absence of functional dystrophin, DMD pathogenesis is driven by the progressive degeneration of muscle fibers, resulting in the development of inflammation and fibrosis that ultimately affect the overall muscle biomechanics. On the opposite end of the spectrum of muscle diseases, age-related sarcopenia is a common disease that affects a growing proportion of the elderly, often leading to frailty and loss of independence. Although characterized by fundamentally different pathological mechanisms, DMD and sarcopenia share the development of progressive muscle weakness and tissue inflammation. The natural compound Cyclo Histidine-Proline (CHP) has been shown to reduce inflammation and fibrosis in a number of metabolic diseases, including steatohepatitis and diabetes. We evaluate here the effects of CHP in DMD and sarcopenia. In two independent studies in the mdx mouse model of DMD, we show that CHP restored muscle contractility and force production, accompanied by a robust reduction of fibrosis and inflammation in skeletal muscle. In the mdx model, CHP furthermore prevented the development of cardiomyopathy and fibrosis in the diaphragm, the two leading causes of death for DMD patients. CHP also attenuated muscle atrophy and functional deterioration in a mouse model of age-related sarcopenia. These data in two different models of muscle dysfunction hence warrant further study of the effects of CHP in muscle pathologies in animal models and eventually in patients.

2024-05-11 | GSE241771 | GEO

Post-transplant (non-alcoholic steatohepatitis) NASH compared with transplanted normal controls

Project description:Non-alcoholic fatty liver disease (NAFLD) encompasses a spectrum of disease that ranges from simple steatosis, to inflammatory form non-alcoholic steatohepatitis (NASH), cirrhosis, and up to hepatocellular carcinoma. While NASH usually takes decades to develop at a rate of one stage per seven years, in the case of post-trasplant NASH (pt-NASH) develops fibrosis much more rapidly, with almost 50% of liver transplant recipients presenting stage 3 fibrosis by 5 years post-transplant. Archived fresh-frozen transplanted liver biopsy samples from four liver biopsy samples with evidence of NASH (2 recurrent and 2 de novo), two with simple steatosis (both de novo), and five with normal histology as controls had their transcriptome sequenced in two batches for deeper coverage.

2022-05-09 | E-MTAB-11688 | biostudies-arrayexpress

Transcriptome profiling of human non-alcoholic fatty liver disease

Project description:Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide. Nonalcoholic steatohepatitis (NASH), the progressive form of NAFLD, and advanced fibrosis are associated with poor outcomes but their molecular pathogenesis is not fully elucidated. Global RNA sequencing of snap frozen liver tissue from 98 patients with biopsy-proven NAFLD was performed. Unsupervised hierarchical clustering well-distinguished NASH from NAFL, and NASH patients exhibited molecular abnormalities reflecting their pathological features. Transcriptomic analysis identified multiple secreted proteins upregulated in NASH and/or advanced fibrosis

2021-05-31 | GSE167523 | GEO

Liver transcriptome of biopsy-proven NAFLD patients at different stages of the disease

Project description:We investigated the hepatic transcriptome of 58 biopsy-proven NAFLD patients at multiple stages of the disease (NAFL, NASH with mild fibrosis, NASH with advanced fibrosis) with the aim of describing the pathophysiological events driving the development and progression of NASH.

2021-04-14 | E-MTAB-9815 | biostudies-arrayexpress

Nitro-fatty acids protect against steatosis and fibrosis during development of nonalcoholic fatty liver disease in mice

Project description:Lack of non-invasive diagnostic tools and effective therapies constitute two of the major hurdles for a bona fide treatment against non-alcoholic steatohepatitis (NASH) progression and/or regression of nonalcoholic fatty liver disease (NAFLD). Nitro-oleic acid (OA-NO2) has been proven effective in multiple experimental models of inflammation and fibrosis. Thus, the potential benefit of in vivo administration of OA-NO2 to treat advanced NAFLD was studied in a model of long-term NASH diet-induced liver damage. Non-invasive imaging (e.g. photoacustic-ultrasound (PA-US)) was pursued to establish advanced experimental NASH in mice in which both steatosis and fibrosis were diagnosed prior experimental OA-NO2 therapy. CLAMS and NMR-based analysis demonstrates that OA-NO2 improves body composition and energy metabolism and inhibits hepatic triglyceride accumulation. PA-US imaging revealed a robust inhibition of liver steatosis and fibrosis by OA-NO2. RNA-sequencing analysis uncovered inflammation and fibrosis as major pathways suppressed by OA-NO2 administration, as well as regulation of lipogenesis and lipolysis pathways, with a robust inhibition of SREBP1-dependent lipogenic gene expression by OA-NO2. Global liver transcriptome in response to OA-NO2 was confirmed in vivo and in isolated hepatocytes. These results were further supported by histological analysis and quantification of lipid accumulation, lobular inflammation (F4/80 staining) and fibrosis (collagen deposition, αSMA staining) as well as established parameters of liver damage (ALT). In vitro studies indicate that OA-NO2 inhibits TG biosynthesis and accumulation in hepatocytes and inhibits fibrogenesis in human stellate cells. Taken together, OA-NO2 improve steatohepatitis and fibrosis and may constitute an effective therapeutic approach against advanced NAFLD that warrants further clinical evaluation.

2019-02-08 | GSE126204 | GEO

Myocardial infarction accelerates hepatic pathological progression of NASH by triggering immunoinflammatory response and induction of periostin

Project description:Patients with non-alcoholic fatty liver disease (NAFLD), especially advanced non-alcoholic steatohepatitis (NASH), have an increased risk of cardiovascular diseases (CVD) due to the production of pro-inflammatory factors, vasoactive and thrombogenic molecules, or insulin resistance and related disorders. While elevated risk and incidence of CVD events in NAFLD/NASH are well established, whether such events will, in turn, influence the pathogenesis of NAFLD remains unknown. Here, we show that myocardial infarction (MI) accelerates the linear hepatic pathological progression of NAFLD. In humans, NAFLD patients who experienced CVD events after their diagnosis of NAFLD show a rapid progression of hepatic fibrosis. In mouse models of NASH, MI promotes hepatic fibrosis, accompanied by elevated circulating Ly6Chi monocytes and their recruitment to the damaged liver tissues. Depleting these cells abrogate MI-induced hepatic pathological effects in mice with NASH. Meanwhile, MI substantially elevates circulating and cardiac periostin contents, which act on hepatocytes and stellate cells to promote hepatic lipid accumulation and fibrosis, finally exacerbating hepatic pathological progression of NASH. Additionally, specific silence of cardiac periostin markedly attenuates MI-induced hepatic pathological progression of mice with NASH. These preclinical and clinical results demonstrate that MI alternates systemic homeostasis and upregulates the production of pro-fibrotic factors, triggering cross-disease communication that accelerates hepatic pathological progression of NAFLD.

2024-06-04 | GSE254698 | GEO

BET Inhibition Improves NASH and Liver Fibrosis

Project description:Non-alcoholic fatty liver disease (NAFLD) is a leading form of chronic liver disease with large unmet need. Non-alcoholic steatohepatitis (NASH), a progressive variant of NAFLD, can lead to fibrosis, cirrhosis, and hepatocellular carcinoma. To identify potential new therapeutics for NASH, we used a computational approach based on Connectivity Map (CMAP) analysis, which pointed us to a potential application of bromodomain and extra-terminal motif (BET) inhibitors for treating NASH. To experimentally validate this hypothesis, we tested a small-molecule inhibitor of the BET family of proteins, GSK1210151A (I-BET151), in the STAM mouse NASH model at two different dosing timepoints (onset of NASH and onset of fibrosis) to assess its potential effectiveness for the treatment of NASH and liver fibrosis. I-BET151 decreased the non-alcoholic fatty liver disease activity score (NAS), a clinical endpoint for assessing the severity of NASH, as well as progression of liver fibrosis and interferon-γ expression. Transcriptional characterization through RNA-sequencing pointed to alterations in molecular mechanisms related to interferon signaling and cholesterol biosynthesis following treatment, as well as reversal of gene expression patterns linked to fibrotic markers. Altogether, these results suggest that inhibition of BET proteins may present a novel therapeutic opportunity in the treatment of NASH and liver fibrosis.

2018-11-27 | GSE114261 | GEO

Gene expression in liver of morbidly obese patients

Project description:Nonalcoholic fatty liver disease (NAFLD) has become the most common cause of liver disease affecting 20-30% of the population in developed countries. NAFLD is strongly associated with abdominal obesity and is recognized as the hepatic manifestation of the metabolic syndrome. In a subgroup of patients with NAFLD inflammation and fibrosis develops, this so-called Non-Alcoholic Steatohepatitis (NASH) may progress to cirrhosis and hepatocellular carcinoma. A multi-hit hypothesis has been proposed in which during the first “hit” fat accumulation occurs in hepatocytes from excessive delivery of fatty acids from adipose tissue, in addition there is an imbalance in lipid synthesis and export. However, the reason why fat accumulation is subsequently followed by inflammation and fibrosis in some patients is poorly understood. We studied the role of gene expression at the transcriptional level using microarray in bariatric patients from whom the liver histology was available. Patients scheduled for bariatric surgery were recruited in Pretoria/South-Africa. At the time of the procedure, tissue samples of the visceral and subcutaneous fat were taken for molecular analysis as well as liver tissue for histology, also full biochemical data was collected. Patients were grouped according histology: group I (<5% steatosis), group II (NAFLD, 30-50% steatosis) and group III (NASH). The 15 samples were used for microarray (nr patients respectively for stages I-II-III: 6-4-5).This dataset is part of the TransQST collection.

2015-07-02 | E-GEOD-59045 | biostudies-arrayexpress

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