bims-faldev 2024-06-09 papers

bims-faldev

Biomed News

on Fatty liver disease and extracellular vesicles

Issue of 2024–06–09
eleven papers selected by
Stepheny Carneiro de Campos Zani, Universidade Estadual de Campinas

Metabolic reprogramming in liver fibrosis.
CD47, a novel YAP target gene, contributes to hepatic stellate cell activation and liver fibrosis induced by high-fat diet.
Egr2 drives the differentiation of Ly6Chi monocytes into fibrosis-promoting macrophages in metabolic dysfunction-associated steatohepatitis in mice.
A suite of genome-engineered hepatic cells provide novel insights into the spatiotemporal metabolism of APOB and APOB-containing lipoprotein secretion.
The adiponectin-derived peptide ALY688 protects against the development of metabolic dysfunction-associated steatohepatitis.
Role and therapeutic perspectives of extracellular vesicles derived from liver and adipose tissue in metabolic dysfunction-associated steatotic liver disease.
Sphingosine d18:1 promotes nonalcoholic steatohepatitis by inhibiting macrophage HIF-2α.
Envisioning how to advance the MASH field.
Association of systemic inflammatory indices with anthropometric measures, metabolic factors, and liver function in non-alcoholic fatty liver disease.
PNPLA3 is a triglyceride lipase that mobilizes polyunsaturated fatty acids to facilitate hepatic secretion of large-sized very low-density lipoprotein.
Metabolism and bioenergetics in the pathophysiology of organ fibrosis.

Cell Metab. 2024 May 27. pii: S1550-4131(24)00179-7. [Epub ahead of print]

Metabolic reprogramming in liver fibrosis.

Paul Horn, Frank Tacke.

  Chronic liver diseases, primarily metabolic dysfunction-associated steatotic liver disease (MASLD), harmful use of alcohol, or viral hepatitis, may result in liver fibrosis, cirrhosis, and cancer. Hepatic fibrogenesis is a complex process with interactions between different resident and non-resident heterogeneous liver cell populations, ultimately leading to deposition of extracellular matrix and organ failure. Shifts in cell phenotypes and functions involve pronounced transcriptional and protein synthesis changes that require metabolic adaptations in cellular substrate metabolism, including glucose and lipid metabolism, resembling changes associated with the Warburg effect in cancer cells. Cell activation and metabolic changes are regulated by metabolic stress responses, including the unfolded protein response, endoplasmic reticulum stress, autophagy, ferroptosis, and nuclear receptor signaling. These metabolic adaptations are crucial for inflammatory and fibrogenic activation of macrophages, lymphoid cells, and hepatic stellate cells. Modulation of these pathways, therefore, offers opportunities for novel therapeutic approaches to halt or even reverse liver fibrosis progression.

Keywords:  ER; FXR; HSC; Kupffer cells; MASH; MASLD; NAFLD; NASH; liver fibrosis; macrophage; resmetirom

DOI:  https://doi.org/10.1016/j.cmet.2024.05.003
Heliyon. 2024 May 30. 10(10): e31621

CD47, a novel YAP target gene, contributes to hepatic stellate cell activation and liver fibrosis induced by high-fat diet.

Ya Li, Lin Dong, Xuecui Yin, Xiaohan Wang, Xiaohui Zhu, Pengyuan Zheng, Youcai Tang.

  Activated hepatic stellate cells (HSCs) have been widely recognized as a primary source of pathological myofibroblasts, leading to the accumulation of extracellular matrix and liver fibrosis. CD47, a transmembrane glycoprotein expressed on the surface of various cell types, has been implicated in non-alcoholic fatty liver disease. However, the precise role of CD47 in HSC activation and the underlying regulatory mechanisms governing CD47 expression remain poorly understood. In this study, we employed single-cell RNA sequencing analysis to investigate CD47 expression in HSCs from mice subjected to a high-fat diet. CD47 silencing in HSCs markedly inhibited the expression of fibrotic genes and promoted apoptosis. Mechanistically, we found that Yes-associated protein (YAP) collaborates with TEAD4 to augment the transcriptional activation of CD47 by binding to its promoter region. Notably, disruption of the interaction between YAP and TEAD4 caused a substantial decrease in CD47 expression in HSCs and reduced the development of high-fat diet-induced liver fibrosis. Our findings highlight CD47 as a critical transcriptional target of YAP in promoting HSC activation in response to a high-fat diet. Targeting the YAP/TEAD4/CD47 signaling axis may hold promise as a therapeutic strategy for liver fibrosis.

Keywords:  CD47; Hepatic stellate cells; High-fat diet; Liver fibrosis; YAP

DOI:  https://doi.org/10.1016/j.heliyon.2024.e31621
Commun Biol. 2024 Jun 03. 7(1): 681

Egr2 drives the differentiation of Ly6Chi monocytes into fibrosis-promoting macrophages in metabolic dysfunction-associated steatohepatitis in mice.

Ayaka Iwata, Juri Maruyama, Shibata Natsuki, Akira Nishiyama, Tomohiko Tamura, Minoru Tanaka, Shigeyuki Shichino, Takao Seki, Toshihiko Komai, Tomohisa Okamura, Keishi Fujio, Masato Tanaka, Kenichi Asano.

Metabolic dysfunction-associated steatohepatitis (MASH), previously called non-alcoholic steatohepatitis (NASH), is a growing concern worldwide, with liver fibrosis being a critical determinant of its prognosis. Monocyte-derived macrophages have been implicated in MASH-associated liver fibrosis, yet their precise roles and the underlying differentiation mechanisms remain elusive. In this study, we unveil a key orchestrator of this process: long chain saturated fatty acid-Egr2 pathway. Our findings identify the transcription factor Egr2 as the driving force behind monocyte differentiation into hepatic lipid-associated macrophages (hLAMs) within MASH liver. Notably, Egr2-deficiency reroutes monocyte differentiation towards a macrophage subset resembling resident Kupffer cells, hampering hLAM formation. This shift has a profound impact, suppressing the transition from benign steatosis to liver fibrosis, demonstrating the critical pro-fibrotic role played by hLAMs in MASH pathogenesis. Long-chain saturated fatty acids that accumulate in MASH liver emerge as potent inducers of Egr2 expression in macrophages, a process counteracted by unsaturated fatty acids. Furthermore, oral oleic acid administration effectively reduces hLAMs in MASH mice. In conclusion, our work not only elucidates the intricate interplay between saturated fatty acids, Egr2, and monocyte-derived macrophages but also highlights the therapeutic promise of targeting the saturated fatty acid-Egr2 axis in monocytes for MASH management.

DOI: https://doi.org/10.1038/s42003-024-06357-5
Cardiovasc Res. 2024 Jun 04. pii: cvae121. [Epub ahead of print]

A suite of genome-engineered hepatic cells provide novel insights into the spatiotemporal metabolism of APOB and APOB-containing lipoprotein secretion.

Amber Meurs, Klevis Ndoj, Marlene van den Berg, Goran Marinković, Matteo Tantucci, Tineke Veenendaal, Jan Albert Kuivenhoven, Judith Klumperman, Noam Zelcer.

   AIMS: APOB-containing very-low-density lipoprotein (VLDL) production, secretion, and clearance by hepatocytes is a central determinant of hepatic and circulating lipid levels. Impairment of any of the aforementioned processes is associated with the development of multiple diseases. Despite the discovery of genes and processes that govern hepatic VLDL metabolism, our understanding of the different mechanistic steps involved is far from complete. An impediment to these studies is the lack of tractable hepatocyte-based systems to interrogate and follow APOB in cells, which the current study addresses.
METHODS AND RESULTS: To facilitate the cellular study of VLDL metabolism, we generated human hepatic HepG2 and Huh-7 cell lines in which CRISPR/Cas9-based genome engineering was used to introduce the fluorescent protein mNeonGreen into the APOB gene locus. This results in the production of APOB100-mNeon that localizes predominantly to the endoplasmic reticulum (ER) and Golgi by immunofluorescence and electron microscopy imaging. The production and secretion of APOB100-mNeon can be quantitatively followed in medium over time, and results in production of lipoproteins that are taken up via the LDLR pathway. Importantly, the production and secretion of APOB-mNeon is sensitive to established pharmacological and physiological treatments, and to genetic modifiers known to influence VLDL production in humans. As a showcase, we used HepG2-APOBmNeon cells to interrogate ER-associated degradation (ERAD) of APOB. Using a dedicated sgRNA library targeting all established membrane-associated ER-resident E3 ubiquitin ligases led to identification of SYNV1 as the E3 responsible for degradation of poorly-lipidated APOB in HepG2 cells.
CONCLUSIONS: In summary, the engineered cells reported here allow the study of hepatic VLDL assembly and secretion, and facilitate spatiotemporal interrogation induced by pharmacologic and genetic perturbations.

Keywords:  APOB; ERAD; HRD1; MASLD; SYVN1; VLDL; hepatocytes; lipoprotein metabolism

DOI:  https://doi.org/10.1093/cvr/cvae121
Clin Transl Sci. 2024 Jun;17(6): e13760

The adiponectin-derived peptide ALY688 protects against the development of metabolic dysfunction-associated steatohepatitis.

Zhe Huang, Hye Kyoung Sung, Xingqun Yan, Shiyu He, Leigang Jin, Qin Wang, Xuerui Wu, Henry H Hsu, Angelica Pignalosa, Kathryn Crawford, Gary Sweeney, Aimin Xu.

Metabolic dysfunction-associated steatohepatitis (MASH) is the severe form of non-alcoholic fatty liver disease which has a high potential to progress to cirrhosis and hepatocellular carcinoma, yet adequate effective therapies are lacking. Hypoadiponectinemia is causally involved in the pathogenesis of MASH. This study investigated the pharmacological effects of adiponectin replacement therapy with the adiponectin-derived peptide ALY688 (ALY688-SR) in a mouse model of MASH. Human induced pluripotent stem (iPS) cell-derived hepatocytes were used to test cytotoxicity and signaling of unmodified ALY688 in vitro. High-fat diet with low methionine and no added choline (CDAHF) was used to induce MASH and test the effects of ALY688-SR in vivo. Histological MASH activity score (NAS) and fibrosis score were determined to assess the effect of ALY688-SR. Transcriptional characterization of mice through RNA sequencing was performed to indicate potential molecular mechanisms involved. In cultured hepatocytes, ALY688 efficiently induced adiponectin-like signaling, including the AMP-activated protein kinase and p38 mitogen-activated protein kinase pathways, and did not elicit cytotoxicity. Administration of ALY688-SR in mice did not influence body weight but significantly ameliorated CDAHF-induced hepatic steatosis, inflammation, and fibrosis, therefore effectively preventing the development and progression of MASH. Mechanistically, ALY688-SR treatment markedly induced hepatic expression of genes involved in fatty acid oxidation, whereas it significantly suppressed the expression of pro-inflammatory and pro-fibrotic genes as demonstrated by transcriptomic analysis. ALY688-SR may represent an effective approach in MASH treatment. Its mode of action involves inhibition of hepatic steatosis, inflammation, and fibrosis, possibly via canonical adiponectin-mediated signaling.

DOI: https://doi.org/10.1111/cts.13760
Artif Cells Nanomed Biotechnol. 2024 Dec;52(1): 355-369

Role and therapeutic perspectives of extracellular vesicles derived from liver and adipose tissue in metabolic dysfunction-associated steatotic liver disease.

Wandi Li, Lili Yu.

  The global epidemic of metabolic diseases has led to the emergence of metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH), which pose a significant threat to human health. Despite recent advances in research on the pathogenesis and treatment of MASLD/MASH, there is still a lack of more effective and targeted therapies. Extracellular vesicles (EVs) discovered in a wide range of tissues and body fluids encapsulate different activated biomolecules and mediate intercellular communication. Recent studies have shown that EVs derived from the liver and adipose tissue (AT) play vital roles in MASLD/MASH pathogenesis and therapeutics, depending on their sources and intervention types. Besides, adipose-derived stem cell (ADSC)-derived EVs appear to be more effective in mitigating MASLD/MASH. This review presents an overview of the definition, extraction strategies, and characterisation of EVs, with a particular focus on the biogenesis and release of exosomes. It also reviews the effects and potential molecular mechanisms of liver- and AT-derived EVs on MASLD/MASH, and emphasises the contribution and clinical therapeutic potential of ADSC-derived EVs. Furthermore, the future perspective of EV therapy in a clinical setting is discussed.

Keywords:  Metabolic dysfunction-associated steatotic liver disease; adipose tissue; adipose-derived stem cell; extracellular vesicle; liver

DOI:  https://doi.org/10.1080/21691401.2024.2360008
Nat Commun. 2024 Jun 04. 15(1): 4755

Sphingosine d18:1 promotes nonalcoholic steatohepatitis by inhibiting macrophage HIF-2α.

Jialin Xia, Hong Chen, Xiaoxiao Wang, Weixuan Chen, Jun Lin, Feng Xu, Qixing Nie, Chuan Ye, Bitao Zhong, Min Zhao, Chuyu Yun, Guangyi Zeng, Yuejian Mao, Yongping Wen, Xuguang Zhang, Sen Yan, Xuemei Wang, Lulu Sun, Feng Liu, Chao Zhong, Pengyan Xia, Changtao Jiang, Huiying Rao, Yanli Pang.

Non-alcoholic steatohepatitis (NASH) is a severe type of the non-alcoholic fatty liver disease (NAFLD). NASH is a growing global health concern due to its increasing morbidity, lack of well-defined biomarkers and lack of clinically effective treatments. Using metabolomic analysis, the most significantly changed active lipid sphingosine d18:1 [So(d18:1)] is selected from NASH patients. So(d18:1) inhibits macrophage HIF-2α as a direct inhibitor and promotes the inflammatory factors secretion. Male macrophage-specific HIF-2α knockout and overexpression mice verified the protective effect of HIF-2α on NASH progression. Importantly, the HIF-2α stabilizer FG-4592 alleviates liver inflammation and fibrosis in NASH, which indicated that macrophage HIF-2α is a potential drug target for NASH treatment. Overall, this study confirms that So(d18:1) promotes NASH and clarifies that So(d18:1) inhibits the transcriptional activity of HIF-2α in liver macrophages by suppressing the interaction of HIF-2α with ARNT, suggesting that macrophage HIF-2α may be a potential target for the treatment of NASH.

DOI: https://doi.org/10.1038/s41467-024-48954-2
Nat Rev Gastroenterol Hepatol. 2024 Jun 04.

Envisioning how to advance the MASH field.

Alina M Allen, Zobair M Younossi, Anna Mae Diehl, Michael R Charlton, Jeffrey V Lazarus.

Since 1980, the cumulative effort of scientists and health-care stakeholders has advanced the prerequisites to address metabolic dysfunction-associated steatotic liver disease (MASLD), a prevalent chronic non-communicable liver disease. This effort has led to, among others, the approval of the first drug specific for metabolic dysfunction-associated steatohepatitis (MASH; formerly known as nonalcoholic steatohepatitis). Despite substantial progress, MASLD is still a leading cause of advanced chronic liver disease, including primary liver cancer. This Perspective contextualizes the nomenclature change from nonalcoholic fatty liver disease to MASLD and proposes important considerations to accelerate further progress in the field, optimize patient-centric multidisciplinary care pathways, advance pharmacological, behavioural and diagnostic research, and address health disparities. Key regulatory and other steps necessary to optimize the approval and access to upcoming additional pharmacological therapeutic agents for MASH are also outlined. We conclude by calling for increased education and awareness, enhanced health system preparedness, and concerted action by policy-makers to further the public health and policy agenda to achieve at least parity with other non-communicable diseases and to aid in growing the community of practice to reduce the human and economic burden and end the public health threat of MASLD and MASH by 2030.

DOI: https://doi.org/10.1038/s41575-024-00938-9
Sci Rep. 2024 06 04. 14(1): 12829

Association of systemic inflammatory indices with anthropometric measures, metabolic factors, and liver function in non-alcoholic fatty liver disease.

Sara Arefhosseini, Taha Aghajani, Helda Tutunchi, Mehrangiz Ebrahimi-Mameghani.

  The present cross-sectional study aimed to explore the relationship between systemic inflammatory indices (SIIs) and anthropometric measures, metabolic, and liver function biomarkers in patients with non-alcoholic fatty liver disease (NAFLD). This study was carried out on 238 NAFLD patients with overweight or obesity, aged 18-55 years. Anthropometric measurements were done and body mass index (BMI), waist-to-hip ratio (WHR), and waist-to-height ratio (WHtR) were estimated. Metabolic factors including serum glucose, lipid profile, liver function biomarkers, and complete blood cell count were assessed after a 24-h fasting state. SIIs including the ratios of neutrophil to lymphocyte (NLR), monocytes to lymphocyte (MLR), platelet to lymphocyte (PLR), and monocytes to high-density lipoprotein cholesterol (MHR) were calculated. Results indicate that apart from PLR, all of the SIIs significantly changed by increasing steatosis severity (all p < 0.05). Moreover, changes in NLR showed a significant association with anthropometric indices including waist circumference (p = 0.032), BMI (p = 0.047), and WHtR (p = 0.002), as well as levels of fasting blood sugar (p = 0.045), triglycerides, (p = 0.025) and low-density lipoprotein cholesterol (p = 0.006). The findings also indicate the relations between lipid profile and all studied SIIs, notably MHR and MLR. All of the SIIs exhibited associations with some liver function indices as well. MHR was positively correlated with the metabolic risk factors of NAFLD while, oppositely, PLR was considered as a preventive marker of NAFLD.

Keywords:  Inflammation; Liver function; Metabolic factors; Non-alcoholic fatty liver disease; Systemic inflammatory indices

DOI:  https://doi.org/10.1038/s41598-024-63381-5
Nat Commun. 2024 Jun 06. 15(1): 4847

PNPLA3 is a triglyceride lipase that mobilizes polyunsaturated fatty acids to facilitate hepatic secretion of large-sized very low-density lipoprotein.

Scott M Johnson, Hanmei Bao, Cailin E McMahon, Yongbin Chen, Stephanie D Burr, Aaron M Anderson, Katja Madeyski-Bengtson, Daniel Lindén, Xianlin Han, Jun Liu.

The I148M variant of PNPLA3 is closely associated with hepatic steatosis. Recent evidence indicates that the I148M mutant functions as an inhibitor of PNPLA2/ATGL-mediated lipolysis, leaving the role of wild-type PNPLA3 undefined. Despite showing a triglyceride hydrolase activity in vitro, PNPLA3 has yet to be established as a lipase in vivo. Here, we show that PNPLA3 preferentially hydrolyzes polyunsaturated triglycerides, mobilizing polyunsaturated fatty acids for phospholipid desaturation and enhancing hepatic secretion of triglyceride-rich lipoproteins. Under lipogenic conditions, mice with liver-specific knockout or acute knockdown of PNPLA3 exhibit aggravated liver steatosis and reduced plasma VLDL-triglyceride levels. Similarly, I148M-knockin mice show decreased hepatic triglyceride secretion during lipogenic stimulation. Our results highlight a specific context whereby the wild-type PNPLA3 facilitates the balance between hepatic triglyceride storage and secretion, and suggest the potential contribution of a loss-of-function by the I148M variant to the development of fatty liver disease in humans.

DOI: https://doi.org/10.1038/s41467-024-49224-x
Free Radic Biol Med. 2024 Jun 03. pii: S0891-5849(24)00510-0. [Epub ahead of print]

Metabolism and bioenergetics in the pathophysiology of organ fibrosis.

Verónica Miguel, Elena Alcalde-Estévez, Belén Sirera, Fernando Rodríguez-Pascual, Santiago Lamas.

  Fibrosis is the tissue scarring characterized by excess deposition of extracellular matrix (ECM) proteins, mainly collagens. A fibrotic response can take place in any tissue of the body and is the result of an imbalanced reaction to inflammation and wound healing. Metabolism has emerged as a major driver of fibrotic diseases. While glycolytic shifts appear to be a key metabolic switch in activated stromal ECM-producing cells, several other cell types such as immune cells, whose functions are intricately connected to their metabolic characteristics, form a complex network of pro-fibrotic cellular crosstalk. This review purports to clarify shared and particular cellular responses and mechanisms across organs and etiologies. We discuss the impact of the cell-type specific metabolic reprogramming in fibrotic diseases in both experimental and human pathology settings, providing a rationale for new therapeutic interventions based on metabolism-targeted antifibrotic agents.

Keywords:  Bioenergetics; Chronic tissue damage; Fibrosis; Inflammation; Metabolism; Mitochondria

DOI:  https://doi.org/10.1016/j.freeradbiomed.2024.06.001