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• W1935068710 abstract "Potential conflict of interest: Nothing to report. This work was supported by the Ministry of Science and Research of the State of North Rhine‐Westphalia (MIWF NRW), the German Federal Ministry of Health (BMG),the Federal Ministry for Research (BMBF) to the Centers for Diabetes Research (DZD e.V.), Helmholtz Alliance Imaging, and Curing Environmental Metabolic Diseases (ICEMED). See Article on Page 870 Approximately 70% of patients with obesity or type 2 diabetes (T2D) have nonalcoholic fatty liver disease (NAFLD). Hepatic steatosis relates not only to hepatic, but also to whole‐body insulin resistance (IR) and even predicts T2D and cardiovascular disease.1 Nevertheless, not all insulin‐resistant or obese persons have steatosis or progress to nonalcoholic steatohepatitis (NASH).1 Therefore, pathogenic interaction between NAFLD and hepatic insulin resistance (HIR) remains controversial.2 The underlying mechanisms can involve extrahepatic factors, such as adipocytokines, but the key factors are intrahepatic inflammatory pathways, altered mitochondrial function, and oxidative and endoplasmatic reticulum (ER) stress.1 Most importantly, augmented lipid availability may increase lipid intermediates, such as fatty acyl‐coenzyme A (FA‐CoA), diacylglycerols (DAGs), and sphingolipids, which cause deleterious effects, previously summarized as lipotoxicity (Fig. 1). Excessive ß‐oxidation with depletion of tricarboxylic acid (TCA) cycle components leads to incomplete lipid oxidation and raises toxic acylcarnitines. There is growing evidence that, rather than one single signal, an imbalance between triglyceride (TG) storage, cellular intermediates, oxidative capacity, and adaptation of mitochondria is the driving force of the connection between NAFLD and IR.5Figure 1: Proposed role of Plin5 as regulator of hepatocellular lipid partitioning in steatosis (A) and in Plin5‐deficient mice (B). Free fatty acids (FFA, FA‐CoA) enter the hepatocyte through the fatty acid transporter (FATP), or arise from de novo lipogenesis, and accumulate as TGs in lipid droplets coated by Plin5 or promote the formation of DAG. Toll‐like receptor (TLR) stimulation by FFAs promotes the synthesis of ceramides, which block insulin signaling (insulin receptor substrate‐2; IRS2). Plin5 binds to ATGL and CGI‐58, thereby inhibiting lipolysis and promoting lipid storage. Plin5 deficiency leads to higher FA‐CoA levels, stimulate mitochondrial biogenesis through PPAR‐α, and increase oxidation within mitochondria (TCA, tricarboxylic cycle). Higher β‐oxidation rates increase the production of ROS and ER stress.In this context, the function of cytoplasmic lipid droplets has gained increasing interest. The TG core of these droplets is surrounded by a phospholipid monolayer coated by a dynamic network of proteins, including the perilipin (Plin) family7 (Fig. 1). In humans, loss‐of‐function mutations of adipocyte‐specific Plin1 cause partial lipodystrophy, severe IR, and steatosis.10 Plin2 and Plin5, mainly expressed in heart and skeletal muscle, are also found in the liver and seem to be involved in droplet assembly and lipid partitioning through peroxisome proliferator‐activated receptor (PPAR) agonists and PPAR‐gamma coactivator 1 alpha.8 In this issue, Wang et al.11 report that Plin5 protein and messenger RNA expression are increased in steatotic livers from humans and obese ob/ob mice. Upon binding to both comparative gene identification 58 (CGI‐58) and adipose triglyceride lipase (ATGL), Plin5 disrupts their interaction, thereby inhibiting ATGL activity. As a result, Plin5‐null mice feature lower hepatic TGs, but increases in hepatic nonesterified fatty acids (FAs) and PPAR‐α, associated with more and smaller mitochondria. Moreover, these mice develop liver injury along with increased markers of lipid peroxidation, ER stress, and inflammation, but without fibrosis. The investigators conclude that the presence of Plin5 protects from lipid‐induced liver injury and thereby from NASH. Of note, Plin5 deficiency is associated with lower hepatic TGs, higher lipid oxidation, and serum ketone bodies, but without any effect on whole‐body glucose tolerance and insulin sensitivity during fasting and after high‐fat feeding. This study provides supporting evidence that Plin5 is involved in hepatic TG formation and raises several questions of whether (1) greater Plin5 expression reflects a mechanism protecting against lipotoxic damage, (2) Plin5 deficiency associates with lipotoxicity leading to IR, and (3) whether this mouse can serve as a model of NAFLD. The greater expression of Plin5 could simply mirror an increased density of lipid droplets in these steatotic livers. In livers of ob/ob mice, Plin5 expression was lower, when compared with Plin2, whose knockout has recently been shown to prevent hepatic ceramide and TG accumulation in dietary‐ and alcoholic‐induced steatosis.12 But, in the absence of data on hepatic expression of PPARs, which are known to control Plin5 expression,9 a protective role of Plin5 up‐regulation against lipotoxicity‐related NAFLD remains speculative. Interestingly, Plin5‐null mice showed features typically associated with HIR, ranging from increased intracellular FA to inflammation, whereas glucose and insulin tolerance tests were comparable to wild‐type mice.11 A recent study on muscle effects of Plin5 deficiency found no alteration of glucose tolerance, but lower muscle and even a trend toward higher hepatic insulin sensitivity using the gold‐standard clamp test.14 In skeletal muscle, this is associated with specific sphingolipids, C16:0‐ and C18:0‐ceramide levels. On the other hand, Plin5‐knockout mice are preserved from diabetes‐induced myocardial failure along with lower DAG levels,15 which resembles the role of specific C18:1‐ and C18:2‐DAGs as mainly responsible for lipid‐mediated and common chronic IR in human muscle.16 Finally, increased serum ketone bodies suggest incomplete ß‐oxidation, which could result in acylcarnitine accumulation. Thus, one would like to know whether the Plin5‐null mice of the present study also feature HIR and accumulation of these lipotoxins. Finally, some aspects of the Plin5‐null mouse make it an attractive candidate as an obesity‐independent model of NASH. In humans with steatosis, mitochondrial function was found to be impaired or even enhanced.5 Whereas these differences may partly reside in the inconsistent use of the term mitochondrial function,6 hepatic lipid oxidation likely adapts to lipid availability. In obese patients, higher lipid fluxes may enhance hepatic oxidative capacity, which is lost in long‐term diabetes and may predispose to NASH.5 The present study does not allow for drawing of firm conclusions on mitochondrial function in Plin5‐null mice.11 Nevertheless, greater FA availability can induce adaptive increases in hepatic energy metabolism and lipid peroxides with concomitant c‐jun N‐terminal kinase activity in liver and DAG/protein kinase C–mediated IR in mouse skeletal muscle.17 Wang et al.11 now provide further evidence that regulation of hepatic substrate oxidation by Plin5 likely determines reactive oxygen species (ROS) production and inflammation as well as oxidation of lipotoxins. However, the absence of fibrosis in these livers limits the enthusiasm for Plin5 knockout as a model to study progression of NAFLD. Taken together, the present study along with recent findings14 point to tissue‐specific roles of Plin5 in liver, skeletal muscle, and heart. The decrease of liver fat in the absence of Plin5 could be seen as “lipodystrophy” of the liver with generation of oxidative and ER stress and redistribution of fat to induce IR in skeletal muscle. But to which extent modulation of Plin5 may serve as a therapeutic target requires further studies in both human and rodent models. Author names in bold designate shared co‐first authorship." @default.
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• W1935068710 title "Perilipin 5: From fatty liver to hepatic lipodystrophy?" @default.
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• W1935068710 doi "https://doi.org/10.1002/hep.27618" @default.
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