A new perspective on NAFLD: Focusing on lipid droplets

Scorletti, Eleonora; Carr, Rotonya M.

doi:10.1016/j.jhep.2021.11.009

Cited by 175 publications

(134 citation statements)

References 129 publications

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“…Alteration of LD's biogenesis, growth, or degradation affects their sizes and numbers in liver cells. Excessive biogenesis and constant growth of LDs are the most distinctive characteristics of NAFLD and are closely associated with the progression of NAFLD towards NASH and cirrhosis (Scorletti and Carr, 2021). LDs are composed of a neutral lipid core surrounded by a phospholipid monolayer associated with various proteins.…”

Section: Introductionmentioning

confidence: 99%

HSD17B13: A Potential Therapeutic Target for NAFLD

Zhang

et al. 2022

Front. Mol. Biosci.

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Nonalcoholic fatty liver disease (NAFLD), especially in its inflammatory form (steatohepatitis, NASH), is closely related to the pathogenesis of chronic liver disease. Despite substantial advances in the management of NAFLD/NASH in recent years, there are currently no efficacious therapies for its treatment. The biogenesis and expansion of lipid droplets (LDs) are critical pathophysiological processes in the development of NAFLD/NASH. In the past decade, increasing evidence has demonstrated that lipid droplet-associated proteins may represent potential therapeutic targets for the treatment of NAFLD/NASH given the critical role they play in regulating the biogenesis and metabolism of lipid droplets. Recently, HSD17B13, a newly identified liver-enriched, hepatocyte-specific, lipid droplet-associated protein, has been reported to be strongly associated with the development and progression of NAFLD/NASH in both mice and humans. Notably, human genetic studies have repeatedly reported a robust association of HSD17B13 single nucleotide polymorphisms (SNPs) with the occurrence and severity of NAFLD/NASH and other chronic liver diseases (CLDs). Here we briefly overview the discovery, tissue distribution, and subcellular localization of HSD17B13 and highlight its important role in promoting the pathogenesis of NAFLD/NASH in both experimental animal models and patients. We also discuss the potential of HSD17B13 as a promising target for the development of novel therapeutic agents for NAFLD/NASH.

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Section: Introductionmentioning

confidence: 99%

HSD17B13: A Potential Therapeutic Target for NAFLD

Zhang

et al. 2022

Front. Mol. Biosci.

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Section: Resultsmentioning

confidence: 99%

“…LDs consist of an inner core of neutral lipids, including TG and sterol esters, a phospholipid monolayer, and LD-associated proteins (LDAPs) [ 6 , 7 , 8 ]. Because LDAPs affect LD function and dynamics [ 6 , 7 , 8 ], we evaluated the effect of Pema and Tofo combination on LDAP expression ( Figure 3 E). The Pema and Tofo combination group showed increased expression of genes related to LD inner core lipid synthesis ( Agpat6 , Dgat1 , and Acat1 ), formation ( Agpat6 , Acsl3 , Mettl7b , and Plin2 ), budding ( Fitm2 and Bscl2 ), stabilization ( Plin4 and Plin5 ), lipolysis ( Pnpla2 , Hsd17b11 , Pcyt1a , and Abhd5 ), expansion ( Agpat3 , Pex3 , and Tcp1 ), and fusion ( Cidea and Cidec ).…”

Section: Resultsmentioning

confidence: 99%

“…LD biogenesis and enhanced esterification of fatty acids play a key role in buffering toxic lipid species [ 6 , 7 , 8 ]. Several reports have indicated that fatty acid accumulation in hepatocytes can lead to cell dysfunction and cell death through endoplasmic reticulum (ER) stress [ 37 , 38 ].…”

Section: Resultsmentioning

confidence: 99%

“…Lipid droplets (LDs) are storage organelles that store neutral lipids such as triglycerides (TGs) and sterol esters during excess energy states and serve as a reservoir of energy supplies during the fasting state [ 6 , 7 , 8 ]. Importantly, not only role in maintaining lipid homeostasis but also buffering function of toxic lipid species have emerged with respect to LD biology.…”

Section: Introductionmentioning

confidence: 99%

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Selective PPARα Modulator Pemafibrate and Sodium-Glucose Cotransporter 2 Inhibitor Tofogliflozin Combination Treatment Improved Histopathology in Experimental Mice Model of Non-Alcoholic Steatohepatitis

Murakami

Sasaki

Asahiyama

et al. 2022

Cells

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Ballooning degeneration of hepatocytes is a major distinguishing histological feature of non-alcoholic steatosis (NASH) progression that can lead to cirrhosis and hepatocellular carcinoma (HCC). In this study, we evaluated the effect of the selective PPARα modulator (SPPARMα) pemafibrate (Pema) and sodium-glucose cotransporter 2 (SGLT2) inhibitor tofogliflozin (Tofo) combination treatment on pathological progression in the liver of a mouse model of NASH (STAM) at two time points (onset of NASH progression and HCC survival). At both time points, the Pema and Tofo combination treatment significantly alleviated hyperglycemia and hypertriglyceridemia. The combination treatment significantly reduced ballooning degeneration of hepatocytes. RNA-seq analysis suggested that Pema and Tofo combination treatment resulted in an increase in glyceroneogenesis, triglyceride (TG) uptake, lipolysis and liberated fatty acids re-esterification into TG, lipid droplet (LD) formation, and Cidea/Cidec ratio along with an increased number and reduced size and area of LDs. In addition, combination treatment reduced expression levels of endoplasmic reticulum stress-related genes (Ire1a, Grp78, Xbp1, and Phlda3). Pema and Tofo treatment significantly improved survival rates and reduced the number of tumors in the liver compared to the NASH control group. These results suggest that SPPARMα and SGLT2 inhibitor combination therapy has therapeutic potential to prevent NASH-HCC progression.

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Lipid Nanoparticle‐Mediated Delivery of CRISPR‐Cas9 Against Rubicon Ameliorates NAFLD by Modulating CD36 Along with Glycerophospholipid Metabolism

Bai,

Nan,

et al. 2024

Advanced Science

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Non‐alcoholic fatty liver disease (NAFLD) is a prominent cause of various chronic metabolic hepatic diseases with limited therapeutics. Rubicon, an essential regulator in lysosomal degradation, is reported to exacerbate hepatic steatosis in NAFLD mice and patients, indicating its probability of being a therapeutic target for NAFLD treatment. In this study, the therapeutic potential of Rubicon blockage is investigated. Lipid nanoparticles carrying Rubicon‐specific CRISPR‐Cas9 components exhibited liver accumulation, cell internalization, and Rubicon knockdown. A single administration of the nanoparticles results in attenuated lipid deposition and hepatic steatosis, with lower circulating lipid levels and decreased adipocyte size in NAFLD mice. Furthermore, the increase of phosphatidylcholine and phosphatidylethanolamine levels can be observed in the NAFLD mice livers after Rubicon silencing, along with regulatory effects on metabolism‐related genes such as CD36, Gpcpd1, Chka, and Lpin2. The results indicate that knockdown of Rubicon improves glycerophospholipid metabolism and thereby ameliorates the NAFLD progression, which provides a potential strategy for NAFLD therapy via the restoration of Rubicon.

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A new perspective on NAFLD: Focusing on lipid droplets

Cited by 175 publications

References 129 publications

HSD17B13: A Potential Therapeutic Target for NAFLD

HSD17B13: A Potential Therapeutic Target for NAFLD

Selective PPARα Modulator Pemafibrate and Sodium-Glucose Cotransporter 2 Inhibitor Tofogliflozin Combination Treatment Improved Histopathology in Experimental Mice Model of Non-Alcoholic Steatohepatitis

Lipid Nanoparticle‐Mediated Delivery of CRISPR‐Cas9 Against Rubicon Ameliorates NAFLD by Modulating CD36 Along with Glycerophospholipid Metabolism

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