cancers Review Lipid Droplet-Associated Factors, PNPLA3, TM6SF2, and HSD17B Proteins in Hepatopancreatobiliary Cancer Yoshiaki Sunami * , Artur Rebelo and Jörg Kleeff Department of Visceral, Vascular and Endocrine Surgery, Martin-Luther-University Halle-Wittenberg, University Medical Center Halle, 06120 Halle, Germany; [email protected] (A.R.); [email protected] (J.K.) * Correspondence: [email protected]; Tel.: +49-345-557-2794 Simple Summary: Aberrant lipid synthesis and reprogrammed lipid metabolism are both associated with the development and progression of pancreatic and liver cancer. Most cells store fatty acids in the form of triacylglycerols in lipid droplets. Lipid droplets are intracellular organelles that not only store neutral lipids, but also play roles as molecular messengers and signaling factors. Some cancer cells accumulate massive amount of lipid droplets. Lipid droplets and lipid droplet-associated factors are further implicated to mediate proliferation, invasion, metastasis, as well as chemotherapy resistance in several types of cancer. This review dissected recent findings on the role of several lipid droplet- associated factors, patatin-like phospholipase domain-containing 3 (PNPLA3), Transmembrane 6 superfamily member 2 (TM6SF2), and 17β-hydroxysteroid dehydrogenase (HSD17B) 11 and 13 as well as their genetic variations in hepatopancreatobiliary diseases, especially cancer. Abstract: Pancreatic and liver cancer are leading causes of cancer deaths, and by 2030, they are projected to become the second and the third deadliest cancer respectively. Cancer metabolism, Citation: Sunami, Y.; Rebelo, A.; especially lipid metabolism, plays an important role in progression and metastasis of many types Kleeff, J. Lipid Droplet-Associated Factors, PNPLA3, TM6SF2, and of cancer, including pancreatic and liver cancer. Lipid droplets are intracellular organelles that HSD17B Proteins in store neutral lipids, but also act as molecular messengers, and signaling factors. It is becoming Hepatopancreatobiliary Cancer. increasingly evident that alterations in the regulation of lipid droplets and their associated factors Cancers 2021, 13, 4391. https:// influence the risk of developing not only metabolic disease but also fibrosis and cancer. In the current doi.org/10.3390/cancers13174391 review article, we summarized recent findings concerning the roles of lipid droplet-associated factors, patatin-like phospholipase domain-containing 3, Transmembrane 6 superfamily member 2, and Academic Editors: Elisa Dalla Pozza 17β-hydroxysteroid dehydrogenase 11 and 13 as well as genetic variants in pancreatic and hepatic and Ilaria Dando diseases. A better understanding of cancer type- and cell type-specific roles of lipid droplet-associated factors is important for establishing new therapeutic options in the future. Received: 26 July 2021 Accepted: 25 August 2021 Keywords: lipid droplets; pancreatic cancer; liver cancer; NAFLD; NASH; fibrosis; PNPLA3; TM6SF2; Published: 31 August 2021 HSD17B; cancer-associated fibroblasts Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- 1. Lipid Synthesis and Lipid Droplets in Pancreatic and Hepatic Cancer iations. Pancreatic cancer is currently the fourth leading cause of cancer deaths in the United States both in females and males [1]; primary liver cancer-related death positions as the seventh place in females and the fifth place in males reported in 2021 [1]. Pancreas and liver cancers are predicted to be the second and third most common cancer death Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. by 2030, respectively [2]. Although recent therapeutic advance such as more effective This article is an open access article palliative, adjuvant, and neo-adjuvant chemotherapy, the overall 5-year survival rate of distributed under the terms and pancreatic cancer is still 10% [1,3]. The overall 5-year survival rate for liver cancer is 20% [1]. conditions of the Creative Commons Both dysregulated lipid synthesis and lipid metabolism reprogramming contribute to the Attribution (CC BY) license (https:// development and progression of pancreatic cancer [4]. Nonalcoholic fatty liver disease creativecommons.org/licenses/by/ (NAFLD) causes hepatocellular carcinoma (HCC) in 13%–38.2% of patients, unrelated to 4.0/). virus and alcohol [5]. Cancers 2021, 13, 4391. https://doi.org/10.3390/cancers13174391 https://www.mdpi.com/journal/cancers Cancers 2021, 13, x FOR PEER REVIEW 2 of 14 (NAFLD) causes hepatocellular carcinoma (HCC) in 13%–38.2% of patients, unrelated to virus and alcohol [5]. For fatty acid (FA) synthesis, ATP-citrate lyase (ACLY) catalyzes the reaction of gen- eration of cytoplasmic acetyl-CoA from citrate. Acetyl-CoA carboxylase (ACC) subse- Cancers 2021, 13, 4391 2 of 13 quently catalyzes conversion into malonyl-CoA. Multi-enzyme protein fatty acid synthase (FASN) converts malonyl-CoA and acetyl CoA coupled to the acyl carrier protein (ACP) domainFor fatty into acid a basic (FA) synthesis, 16-carbon ATP-citrate saturated lyase FA, (ACLY) palmitic catalyzes acid the [4,6,7]. reaction On of gener- the cytosolic side of ation of cytoplasmic acetyl-CoA from citrate. Acetyl-CoA carboxylase (ACC) subsequently catalyzesthe endoplasmic conversion intoreticulum malonyl-CoA. (ER), Multi-enzymelonger FAs ar proteine produced. fatty acid Several synthase types (FASN) of fatty acid de- Δ9 convertssaturases malonyl-CoA such as and-stearoyl-CoA acetyl CoA coupled desaturase to the acyl (SCD) carrier introduce protein (ACP) carbon domain double bonds. SCD intois the a basic rate-limiting 16-carbon enzyme saturated catalyzing FA, palmitic mainly acid [4,6 the,7]. synthesis On the cytosolic of monounsaturated side of the 16- or 18- endoplasmiccarbons molecules reticulum palmitoleate (ER), longer FAs and are oleate produced. from Several palmitoyl-CoA types of fatty and acid stearoyl-CoA, desat- respec- 9 urasestively such [4,6,7]. as D Most-stearoyl-CoA cells store desaturase FAs in (SCD)the form introduce of triacylglycerols carbon double bonds. (TAGs) SCD in the lipid drop- is the rate-limiting enzyme catalyzing mainly the synthesis of monounsaturated 16- or 18-carbonslets (LDs). molecules Glycerol-3-phosphate palmitoleate and oleateacyltransferas from palmitoyl-CoAe (GPAT) and catalyzes stearoyl-CoA, the first re- step of synthe- spectivelysis of TAG, [4,6 ,by7]. the Most acylation cells store of FAs glycerol-3-pho in the form of triacylglycerolssphate and acyl-CoA (TAGs) in to the synthesize lipid lysophos- dropletsphatidic (LDs). acid Glycerol-3-phosphate(LPA) (Figure 1) [8]. acyltransferase GPAT1 and (GPAT)GPAT2 catalyzes are localized the first in step the of outer membrane synthesisof mitochondria. of TAG, by theGPAT3 acylation and of GPAT4 glycerol-3-phosphate are localized and in acyl-CoA the ER tomembrane synthesize [9]. It has been lysophosphatidic acid (LPA) (Figure1)[ 8]. GPAT1 and GPAT2 are localized in the outer membraneshown that of mitochondria. GPAT4 re-localizes GPAT3 and from GPAT4 the are ER localized to a subset in the ER of membrane forming [9 LDs]. It has and mediates LD beengrowth shown [10]. that Expression GPAT4 re-localizes of GPAT1 from the is ER high to a in subset liver of formingand adipose LDs and tissues, mediates GPAT3 plays an LDimportant growth [10 role]. Expression in TAG of synthesis GPAT1 is highin white in liver adipose and adipose tissue tissues, (WAT), GPAT3 and plays GPAT4 an is required importantfor the production role in TAG synthesis of TAGs in white in the adipose mammary tissue (WAT), gland and [9]. GPAT4 GPAT1-deficient is required for mice (global the production of TAGs in the mammary gland [9]. GPAT1-deficient mice (global knockout, knockout, Gpat1−/−) have reduced susceptibility to hepatotoxin diethylnitrosoamine Gpat1−/−) have reduced susceptibility to hepatotoxin diethylnitrosoamine (DEN)-induced liver(DEN)-induced tumorigenesis liver [11]. GPAT2tumorigenesis is highly expressed [11]. GPAT2 in several is highly human cancersexpressed such in as several human melanoma,cancers such lung, as prostate, melanoma, and breast lung, cancer prostate, [12]. GPAT3 andexpression breast cancer is associated [12]. GPAT3 with a expression is shorterassociated overall with survival a shorter of endometrial overall cancer survival patients of endometrial [13]. cancer patients [13]. FigureFigure 1. Substrates1. Substrates and keyand enzymes key enzymes in triacylglycerol in triacylglycerol synthesis. AGPAT: synthesis. Acylglycerolphosphate AGPAT: Acylglycerolphosphate acyltransferase,acyltransferase, DGAT: DGAT: Diacylglycerol Diacylglycerol acyltransferase, acyltransferase, ER: Endoplasmic ER: reticulum, Endoplasmic GPAT: Glycerol-3-reticulum, GPAT: Glyc- phosphateerol-3-phosphate acyltransferase. acyltransferase. LPA is converted into phosphatidic acid (PA) via the acylglycerolphosphate acyl- transferaseLPA (AGPAT) is converted family (Figureinto phosphatidic1). There are eleven acid known (PA) isoformsvia the ofacylglycerolphosphate AGPAT, each acyl- encodedtransferase by a different(AGPAT) gene family [14]. A (Figure comparative 1). There meta-profiling are eleven analysis known of fourteen isoforms dif- of AGPAT, each ferentencoded tumor by types a different (bladder, gene breast, [14]. central A comparative nervous system, meta-profiling colorectal, leukemia, analysis lung, of fourteen dif- lymphoma,ferent tumor melanoma, types mesothelioma,(bladder, breast, ovary, central