International Journal of Molecular Sciences Review Understanding the Role of Perilipin 5 in Non-Alcoholic Fatty Liver Disease and Its Role in Hepatocellular Carcinoma: A Review of Novel Insights Paola Berenice Mass Sanchez, Marinela Krizanac, Ralf Weiskirchen * and Anastasia Asimakopoulos * Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry (IFMPEGKC), RWTH University Hospital Aachen, D-52074 Aachen, Germany; [email protected] (P.B.M.S.); [email protected] (M.K.) * Correspondence: [email protected] (R.W.); [email protected] (A.A.) Abstract: Consumption of high-calorie foods, such as diets rich in fats, is an important factor leading to the development of steatohepatitis. Several studies have suggested how lipid accumulation creates a lipotoxic microenvironment for cells, leading cells to deregulate their transcriptional and transla- tional activity. This deregulation induces the development of liver diseases such as non-alcoholic fatty liver disease (NAFLD) and subsequently also the appearance of hepatocellular carcinoma (HCC) which is one of the deadliest types of cancers worldwide. Understanding its pathology and studying new biomarkers with better specificity in predicting disease prognosis can help in the personalized treatment of the disease. In this setting, understanding the link between NAFLD and HCC progression, the differentiation of each stage in between as well as the mechanisms underlying this process, are vital for development of new treatments and in exploring new therapeutic targets. Citation: Mass Sanchez, P.B.; Perilipins are a family of five closely related proteins expressed on the surface of lipid droplets (LD) in Krizanac, M.; Weiskirchen, R.; several tissues acting in several pathways involved in lipid metabolism. Recent studies have shown Asimakopoulos, A. Understanding that Plin5 depletion acts protectively in the pathogenesis of liver injury underpinning the importance the Role of Perilipin 5 in Non-Alcoholic Fatty Liver Disease of pathways associated with PLIN5. PLIN5 expression is involved in pro-inflammatory cytokine and Its Role in Hepatocellular regulation and mitochondrial damage, as well as endoplasmic reticulum (ER) stress, making it critical Carcinoma: A Review of Novel target of the NAFLD-HCC studies. The aim of this review is to dissect the recent findings and Insights. Int. J. Mol. Sci. 2021, 22, 5284. functions of PLIN5 in lipid metabolism, metabolic disorders, and NAFLD as well as the progression https://doi.org/10.3390/ijms22105284 of NAFLD to HCC. Academic Editor: Anna Fracanzani Keywords: perilipin 5; non-alcoholic liver disease; fatty liver; hepatocellular carcinoma; cancer Received: 24 March 2021 Accepted: 16 May 2021 Published: 17 May 2021 1. Introduction Lipid accumulation in the liver plays a pivotal role in the pathogenesis of NAFLD Publisher’s Note: MDPI stays neutral that might result from dysfunction of cellular lipid trafficking and lipid droplet forma- with regard to jurisdictional claims in published maps and institutional affil- tion. The accepted model of LD formation is based on the biosynthesis of neutral lipids iations. (e.g., triacylglycerides, TAGs) by esterification of fatty acids (FA) into diacylglycerol or sterols [1,2]. The enzymes involved in this biosynthesis of sterols are acetyl-CoA acetyl- transferases 1 and 2 (ACAT1 and ACAT2), whereas TAGs are the product of diacylglycerol acyltransferases (DGAT1 and DGAT2). Once TAG accumulates in the ER, a vesicle of lipids is formed in the ER membrane and LDs are released. Typically, the LD surface is covered Copyright: © 2021 by the authors. with a monolayer of phospholipids and proteins [1,2]. Several enzymes are located in ER, Licensee MDPI, Basel, Switzerland. helping the formation, stabilization, and degradation of LDs. These proteins belong to This article is an open access article distributed under the terms and the perilipin/PAT family, the Ras superfamily of GTPases (Rab), and ADP-ribosylation conditions of the Creative Commons factor1-coat protein complex I (Arf-COPI) [3]. In this context, the general structure of LD Attribution (CC BY) license (https:// consists of a central core of TAG and cholesterol esters, while a peripheral monolayer is creativecommons.org/licenses/by/ composed of phospholipids with attached proteins with structural and functional roles as 4.0/). depicted in Figure1[1]. Int. J. Mol. Sci. 2021, 22, 5284. https://doi.org/10.3390/ijms22105284 https://www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2021, 22, 5284 2 of 18 Int. J. Mol. Sci. 2021, 22, 5284 TAG and cholesterol esters, while a peripheral monolayer is composed of phospholipids2 of 18 with attached proteins with structural and functional roles as depicted in Figure 1 [1]. FigureFigure 1.1. LipidLipid dropletdroplet formationformation and and excessive excessive accumulation accumulation leads leads to hepaticto hepatic pathological pathological con- conditions.ditions. TAG TAG accumulation accumulation in the in ERthe membrane, ER membra accompaniedne, accompanied by the actionby the ofaction different of different proteins, proteins,leads to LD leads formation. to LD formation. This excessive This accumulation excessive accumulation results in impairment results in inimpairment storage of LDin storage in several of LDtissues in several resulting tissues in pathological resulting in conditions pathological such cond as non-alcoholicitions such as fatty non-alcoholic liver disease. fatty Colorful liver disease. spheres Colorful spheres around LD represent perilipins, Rab proteins, and Arf-COPI proteins. ER, around LD represent perilipins, Rab proteins, and Arf-COPI proteins. ER, endoplasmic reticulum; endoplasmic reticulum; LD, lipid droplet; TAG, triacylglyceride. LD, lipid droplet; TAG, triacylglyceride. PerilipinsPerilipins werewere initiallyinitially localized localized in in the the phospholipid phospholipid monolayer monolayer of LDs of LDs in the in 1990s the 1990s[4–6] [4–6]and it and was it not was until not 2010 until that 2010 the “perilipinthat the “perilipin family protein: family PAT protein: protein” PAT was protein” suggested was to suggestedunify the nameto unify of this the family name [of7]. this Perilipins family are [7]. a Perilipins family comprising are a family five distinctcomprising proteins, five distinctwhose expressionproteins, whose varies expression depending varies on the depending tissue. PLIN1 on the presents tissue. its PLIN1 major presents expression its majorin white expression adipocyte in tissuewhite (WAT).adipocyte It cantissue even (W beAT). expressed It can even in brownbe expressed adipocyte in brown tissue adipocyte(BAT) or cardiac tissue muscle(BAT) andor cardiac its functions muscle include and its hormone-induced functions include lipolysis hormone-induced and large LD lipolysisstabilization and [ 8large,9]. PLIN2 LD stabilization is mainly expressed [8,9]. PLIN2 in liver is and mainly pre-adipocytes expressed and in isliver involved and pre-adipocytesin adipocyte differentiation, and is involved small in LD adipocyt formatione differentiation, and stabilization small [9,10 ].LD PLIN3 formation expression and stabilizationis ubiquitous [9,10]. and the PLIN3 protein expression functions is as ubiquitous a LD stabilizer and and the isprotein necessary functions for intracellular as a LD stabilizerlipid trafficking and is [ 9necessary]. The fourth for member,intracellular PLIN4, lipid is expressedtrafficking in [9]. WAT The and fourth skeletal member, muscle PLIN4,and is involved is expressed in human in WAT adipocyte and skeletal differentiation muscle [and9,11 ].is PLIN5involved is expressed in human in adipocyte oxidative differentiationtissues such as cardiac[9,11]. PLIN5 muscle, is BAT, expressed skeletal in muscle, oxidative and livertissues and such is functionally as cardiac linkedmuscle, to BAT,LD stabilization skeletal muscle, and FA and supply liver to and mitochondria is functionally [9]. linked to LD stabilization and FA supplyNAFLD to mitochondria is characterized [9]. by augmented accumulation of hepatic LD, which is in line withNAFLD increased is PLIN5characterized expression by augmented [12]. Recently, accumulation alterations of in hepatic lipid metabolism LD, which haveis in alsoline withbeen increased proposed PLIN5 as a new expression hallmark [12]. of cancer Recently, [13– alterations15]. Moreover, in lipid several metabolism cellular processeshave also beensuch proposed as oxidative as a stress, new hallmark ER stress, of and cancer inflammation [13–15]. Moreover, have been several related cellular to non-alcoholic processes suchsteatohepatitis as oxidative (NASH) stress, theER progressedstress, and forminflammation of NAFLD have [16 ,been17] as related well as to to non-alcoholic cancer devel- steatohepatitisopment and progression (NASH) the [18 ,progressed19]. Meanwhile, form PLIN5of NAFLD has indeed [16,17] been as well implicated as to cancer in the developmentregulation of and lipid progression and glucose [18,19]. homeostasis Meanwhile, and many PLIN5 cellular has indeed processes been suchimplicated as oxida- in thetive regulation stress, ER stress,of lipid inflammation, and glucose andhomeosta autophagysis and [12 ,many20–30 ].cellular This evidence processes once such again as oxidativesupports thestress, notion ER thatstress, PLIN5 inflammation, could play and a direct autophagy role in transition [12,20–30]. from This NAFLD evidence to HCC.once againTherefore, supports it was the suggested notion