Perilipin-2 Deletion Impairs Hepatic Lipid Accumulation by Interfering with Sterol Regulatory Element-binding Protein (SREBP) Activation and Altering the Hepatic Lipidome

Libby, Andrew E.; Bales, Elise S.; Orlicky, David J.; McManaman, James L.

doi:10.1074/jbc.m116.759795

Cited by 78 publications

(93 citation statements)

References 72 publications

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“…RNA extraction, cDNA synthesis, and qRT‐PCR analyses were performed as described (Libby et al . ). Fresh liver tissue was snap‐frozen and stored at −80°C until use.…”

Section: Methodsmentioning

confidence: 97%

“…Hepatic lipids were analysed according to published procedures (Libby et al . ; Perreault et al . ).…”

Section: Methodsmentioning

confidence: 99%

“…; Libby et al . ) in high fat diet and genetic mouse models of obesity. Plin2 lipid storage functions as determinants of obesity‐associated metabolic disorders are not fully understood, and the extent to which hepatocyte‐specific actions of Plin2 determine obesity‐associated NAFLD pathophysiology is uncertain.…”

Section: Introductionmentioning

confidence: 99%

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Perilipin‐2 promotes obesity and progressive fatty liver disease in mice through mechanistically distinct hepatocyte and extra‐hepatocyte actions

Orlicky

Libby

Bales

et al. 2019

The Journal of Physiology

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Key points Wild‐type mice and mice with hepatocyte‐specific or whole‐body deletions of perilipin‐2 (Plin2) were used to define hepatocyte and extra‐hepatocyte effects of altered cellular lipid storage on obesity and non‐alcoholic fatty liver disease (NAFLD) pathophysiology in a Western‐diet (WD) model of these disorders. Extra‐hepatocyte actions of Plin2 are responsible for obesity, adipose inflammation and glucose clearance abnormalities in WD‐fed mice. Hepatocyte and extra‐hepatic actions of Plin2 mediate fatty liver formation in WD‐fed mice through distinct mechanisms. Hepatocyte‐specific actions of Plin2 are primary mediators of immune cell infiltration and fibrotic injury in livers of obese mice. Abstract Non‐alcoholic fatty liver disease (NAFLD) is an obesity‐ and insulin resistance‐related metabolic disorder with progressive pathology. Perilipin‐2 (Plin2), a ubiquitously expressed cytoplasmic lipid droplet scaffolding protein, is hypothesized to contribute to NAFLD in humans and rodent models through effects on cellular lipid metabolism. In this study, we delineate hepatocyte‐specific and extra‐hepatocyte Plin2 mechanisms regulating the effects of obesity and insulin resistance on NAFLD pathophysiology in mice fed an obesogenic Western‐style diet (WD). Total Plin2 deletion (Plin2‐Null) fully protected WD‐fed mice from obesity, insulin resistance, adipose inflammation, steatohepatitis (NASH) and liver fibrosis found in WT animals. Hepatocyte‐specific Plin2 deletion (Plin2‐HepKO) largely protected against NASH and fibrosis and partially protected against steatosis in WD‐fed animals, but it did not protect against obesity, insulin resistance, or adipose inflammation. Significantly, total or hepatocyte‐specific Plin2 deletion impaired WD‐induced monocyte recruitment and pro‐inflammatory macrophage polarization found in livers of WT mice. Analyses of the molecular and cellular processes mediating steatosis, inflammation and fibrosis identified differences in total and hepatocyte‐specific actions of Plin2 on the mechanisms promoting NAFLD pathophysiology. Our results demonstrate that hepatocyte‐specific actions of Plin2 are central to the initiation and pathological progression of NAFLD in obese and insulin‐resistant mice through effects on immune cell recruitment and fibrogenesis. Conversely, extra‐hepatocyte Plin2 actions promote NAFLD pathophysiology through effects on obesity, inflammation and insulin resistance. Our findings provide new insight into hepatocyte and extra‐hepatocyte mechanisms underlying NAFLD development and progression.

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“…RNA extraction, cDNA synthesis, and qRT‐PCR analyses were performed as described (Libby et al . ). Fresh liver tissue was snap‐frozen and stored at −80°C until use.…”

Section: Methodsmentioning

confidence: 97%

“…Hepatic lipids were analysed according to published procedures (Libby et al . ; Perreault et al . ).…”

Section: Methodsmentioning

confidence: 99%

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Perilipin‐2 promotes obesity and progressive fatty liver disease in mice through mechanistically distinct hepatocyte and extra‐hepatocyte actions

Orlicky

Libby

Bales

et al. 2019

The Journal of Physiology

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“…Perilipin 2 null mice have reduced triacylglycerol storage in liver, particularly when the mice are fed a high fat diet, altered mammary gland development and lactation, and protection against obesity with browning of white adipose tissue in mice fed a high fat (103–107). Interestingly, the consequent reduction in liver triacylglycerol has no major effect on the packaging or secretion of very low density lipoproteins (103), although the loss of perilipin 2 in hepatocytes promotes large scale changes in the expression of lipogenic genes that are the targets of SREBP-1 and SREBP-2 (104). Complicating our understanding of perilipin 2 function, a recent study reported that mice with liver-specific deletion of perilipin 2 are not protected against hepatic steatosis when fed a high fat (Western) diet 2 , implying a systemic mechanism of hepatic protection.…”

Section: Perilipins Control Lipolysis Of Stored Neutral Lipids By mentioning

confidence: 99%

The perilipin family of lipid droplet proteins: Gatekeepers of intracellular lipolysis

Sztalryd

Brasaemle

2017

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

400

388

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Lipid droplets in chordates are decorated by two or more members of the perilipin family of lipid droplet surface proteins. The perilipins sequester lipids by protecting lipid droplets from lipase action. Their relative expression and protective nature is adapted to the balance of lipid storage and utilization in specific cells. Most cells of the body have tiny lipid droplets with perilipins 2 and 3 at the surfaces, whereas specialized fat-storing cells with larger lipid droplets also express perilipins 1, 4, and/or 5. Perilipins 1, 2, and 5 modulate lipolysis by controlling the access of lipases and co-factors of lipases to substrate lipids stored within lipid droplets. Although perilipin 2 is relatively permissive to lipolysis, perilipins 1 and 5 have distinct control mechanisms that are altered by phosphorylation. Here we evaluate recent progress toward understanding functions of the perilipins with a focus on their role in regulating lipolysis and autophagy.

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“…In particular, liver of Plin2‐KO mice displays a significant decrease of two important key regulators of lipid synthesis: SREBP1 and DGAT2, suggesting a role for Plin2 in the control of lipid homeostasis‐related genes. Indeed, Plin2 deletion dramatically reduces TAG and cholesterol levels as well as desaturation and elongation of hepatic neutral lipid species in liver . Moreover, a recent work in Drosophila showed that dHDAC6‐dependent Plin2 degradation reduces age‐dependent ectopic fat accumulation and protects the organism from tissue dysfunction during ageing .…”

Section: Introductionmentioning

confidence: 99%

Muscle‐specific Perilipin2 down‐regulation affects lipid metabolism and induces myofiber hypertrophy

Conte

Armani

Conte

et al. 2018

J cachexia sarcopenia muscle

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Background Perilipin2 (Plin2) belongs to a family of five highly conserved proteins, known for their role in lipid storage. Recent data indicate that Plin2 has an important function in cell metabolism and is involved in several human pathologies, including liver steatosis and Type II diabetes. An association between Plin2 and lower muscle mass and strength has been found in elderly and inactive people, but its function in skeletal muscle is still unclear. Here, we addressed the role of Plin2 in adult muscle by gain and loss of function experiments. Methods By mean of in vivo Plin2 down‐regulation (shPlin2) and overexpression (overPlin2) in murine tibialis anterior muscle, we analysed the effects of Plin2 genetic manipulations on myofiber size and lipid composition. An analysis of skeletal muscle lipid composition was also performed in vastus lateralis samples from young and old patients undergoing hip surgery. Results We found that Plin2 down‐regulation was sufficient to induce a 30% increase of myofiber cross‐sectional area, independently of mTOR pathway. Alterations of lipid content and modulation of genes involved in lipid synthesis occurred in hypertrophic muscles. In particular, we showed a decrease of triglycerides, ceramides, and phosphatidylcoline:phosphatidylethanolamine ratio, a condition known to impact negatively on muscle function. Plin2 overexpression did not change fibre size; however, lipid composition was strongly affected in a way that is similar to that observed in human samples from old patients. Conclusions Altogether these data indicate that Plin2 is a critical mediator for the control of muscle mass, likely, but maybe not exclusively, through its critical role in the regulation of intracellular lipid content and composition.

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Perilipin-2 Deletion Impairs Hepatic Lipid Accumulation by Interfering with Sterol Regulatory Element-binding Protein (SREBP) Activation and Altering the Hepatic Lipidome

Cited by 78 publications

References 72 publications

Perilipin‐2 promotes obesity and progressive fatty liver disease in mice through mechanistically distinct hepatocyte and extra‐hepatocyte actions

Perilipin‐2 promotes obesity and progressive fatty liver disease in mice through mechanistically distinct hepatocyte and extra‐hepatocyte actions

The perilipin family of lipid droplet proteins: Gatekeepers of intracellular lipolysis

Muscle‐specific Perilipin2 down‐regulation affects lipid metabolism and induces myofiber hypertrophy

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