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Accumulation of PNPLA3 on Lipid Droplets Is the Basis of Associated Hepatic Steatosis

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Accumulation of PNPLA3 on Lipid Droplets Is the Basis of Associated Hepatic Steatosis Accumulation of PNPLA3 on lipid droplets is the basis of associated hepatic steatosis Soumik BasuRaya, Yang Wanga, Eriks Smagrisa, Jonathan C. Cohenb,1, and Helen H. Hobbsa,b,c,1 aDepartment of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX 75390; bDepartment of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390; and cHoward Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390 Contributed by Helen H. Hobbs, March 19, 2019 (sent for review February 4, 2019; reviewed by Edward A. Fisher and Rudi Zechner) Fatty liver disease (FLD) is a disorder in which accumulation of causes steatosis whereas overexpression of the wild-type (WT) triglycerides (TGs) in the liver can lead to inflammation, fibrosis, and protein does not (15). In KI mice that express PNPLA3(148M) cirrhosis. Previously, we identified a variant (I148M) in patatin-like or PNPLA3(47A), the levels of PNPLA3 on hepatic lipid drop- phospholipase domain-containing protein 3 (PNPLA3) that is strongly lets (LDs) are ∼40-fold higher than those in WT mice, despite associated with FLD, but the mechanistic basis for the association similar levels of PNPLA3 mRNA in the two lines (16). A similar remains elusive. Although PNPLA3 has TG hydrolase activity in vitro, accumulation of PNPLA3 protein was observed in transgenic inactivation or overexpression of the WT protein in mice does not mice expressing human PNPLA3(148M) compared with mice cause steatosis. In contrast, expression of two catalytically defective expressing the WT transgene (15). The massive increase in forms of PNPLA3 (I148M or S47A) in sucrose-fed mice causes accumu- PNPLA3(148M and 47A) levels appears to be due to decreased lation of both PNPLA3 and TGs on hepatic lipid droplets (LDs). To ubiquitylation of the mutant proteins, which leads to decreased determine if amassing PNPLA3 on LDs is a cause or consequence of proteasomal degradation (18). steatosis, we engineered a synthetic isoform of PNPLA3 that uncou- Here we ask whether accumulation of PNPLA3(148M or 47A) ples protein accumulation from loss of enzymatic activity. Expression on LDs is a cause or consequence of the associated steatosis. If of a ubiquitylation-resistant form of PNPLA3 in mice caused accumu- accumulation of PNPLA3 per se is causal, then accumulation of lation of PNPLA3 on hepatic LDs and development of FLD. Lowering the WT protein, which is usually maintained at low levels (16), PNPLA3 levels by either shRNA knockdown or proteolysis-targeting should result in FLD. Conversely, reduction in the amount of MEDICAL SCIENCES chimera (PROTAC)-mediated degradation reduced liver TG content in PNPLA3(148M) should eliminate the FLD phenotype. To test mice overexpressing PNPLA3(148M). Taken together, our results show this hypothesis, we used two complementary strategies: First, we that the steatosis associated with PNPLA3(148M) is caused by accu- engineered a form of the WT protein that retained activity but mulation of PNPLA3 on LDs. evaded proteasomal degradation, and thus accumulated to high levels on LDs. Expression of this isoform caused hepatic steatosis PNPLA3 | fatty liver disease | lipid droplet | autophagy | proteasome in WT mice. Second, we reduced levels of PNPLA3(148M) on LDs using two different methods: (i) shRNA to knock down PNPLA3 onalcoholic fatty liver disease (FLD) is a burgeoning met- expression, and (ii) proteolysis-targeting chimera (PROTAC)-mediated Nabolic disorder in which features of alcohol-associated liver degradation of Halo-tagged PNPLA3(148M). Both strategies disease develop in individuals who consume little or no alcohol lowered PNPLA3 levels on LDs and reduced hepatic steatosis. (1). Accumulation of triglycerides (TGs) in the liver (hepatic steatosis) is the first stage of the disorder. In a subset of individuals, Significance steatosis is associated with an inflammatory response (steatohepatitis) thatcanprogresstocirrhosisandeven hepatocellular carcinoma (2). A sequence variant (I148M) in PNPLA3 is a major genetic risk The primary risk factor for nonalcoholic FLD is obesity, but genetic factor for nonalcoholic fatty liver disease. Previously, we factors play a major role in susceptibility (and resistance) to the showed that PNPLA3(148M) evades ubiquitylation-mediated – disorder (2 5). Previously, we identified a nonsynonymous vari- degradation and accumulates to high levels on lipid droplets ant (I148M) in patatin-like phospholipase domain-containing (LDs). Here we address how this accumulation is related to protein 3 (PNPLA3) that is associated with the full spectrum steatosis. We generated an active, ubiquitylation-resistant of both alcoholic and nonalcoholic FLD (6–10). Although isoform that accumulated on LDs and increased hepatic tri- PNPLA3(148M) is the most common and strongest genetic risk glyceride levels when expressed in livers of mice. Conversely, factor for nonalcoholic FLD (3, 11), the mechanism by which this depletion of PNPLA3 resolved the excess hepatic fat accumu- variant increases liver TG levels remains elusive. lation associated with expression of PNPLA3(148M). Our results In vitro assays using purified recombinant PNPLA3 indicate provide direct evidence that accumulation of PNPLA3 per se that the enzyme has TG hydrolase activity that is reduced ∼80% causes fatty liver, and that depletion of the protein is a po- by the I148M substitution (12). Loss of PNPLA3-mediated TG tential strategy for therapeutic intervention. hydrolase activity alone is unlikely to cause hepatic steatosis, − − since Pnpla3 / mice do not have increased liver TG levels (13, Author contributions: S.B.R., Y.W., E.S., J.C.C., and H.H.H. designed research; S.B.R. and 14). Overexpression of PNPLA3(148M), but not PNPLA3(WT), Y.W. performed research; S.B.R., Y.W., and E.S. contributed new reagents/analytic tools; S.B.R., Y.W., and H.H.H. analyzed data; and S.B.R., Y.W., E.S., J.C.C., and H.H.H. wrote results in hepatic steatosis (15). Moreover, 148M knockin (KI) the paper. 148M/M mice (Pnpla3 ) develop FLD when challenged with a high- Reviewers: E.A.F., New York University School of Medicine; and R.Z., University of Graz. sucrose diet (HSD) (16), which stimulates PNPLA3 expression in The authors declare no conflicts of interest. liver (17). A similar phenotype is seen in mice expressing a 47A/A This open access article is distributed under Creative Commons Attribution-NonCommercial- catalytically dead form of the protein (Pnpla3 ) (16). Thus, NoDerivatives License 4.0 (CC BY-NC-ND). the FLD associated with PNPLA3(148M) requires two condi- 1To whom correspondence may be addressed. Email: jonathan.cohen@utsouthwestern. −/− tions: (i) the protein must be expressed (since Pnpla3 mice do edu or [email protected]. not develop hepatic steatosis), and (ii) the expressed protein This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. must have reduced TG hydrolase activity, since overexpression of 1073/pnas.1901974116/-/DCSupplemental. catalytically impaired forms of PNPLA3 (I148M and S47A) Published online April 24, 2019. www.pnas.org/cgi/doi/10.1073/pnas.1901974116 PNAS | May 7, 2019 | vol. 116 | no. 19 | 9521–9526 Downloaded by guest on September 23, 2021 Results Chloroquine treatment resulted in comparable increases in levels of Inhibition of Autophagy Promotes Accumulation of PNPLA3. Pre- p62 in the two lines of transgenic mice. Despite the increased WT viously, we showed that PNPLA3(WT) is polyubiquitylated and PNPLA3 levels in the PNPLA3Tg mice, no change was seen in degraded by proteasomes (18). Treatment with the proteasome the level of hepatic TGs (Fig. 1A, Lower). inhibitor bortezomib results in an increase in hepatic PNPLA3 in Since chloroquine has effects on protein degradation that are WT mice but not in mice expressing the 148M isoform (18). In independent of autophagy (22), we inactivated autophagy more contrast, treatment with an inhibitor of macroautophagy, 3- specifically by genetically depleting autophagy-related 7 (Atg7), a key component of the autophagy machinery (23). Sucrose-fed methyladenine (3-MA), failed to alter PNPLA3 levels (18). How- − − Pnpla3 / (13, 14) and WT mice were infected with recombinant ever, the efficacy of 3-MA as a macroautophagy inhibitor has been adeno-associated viruses (AAVs) expressing either an shRNA disputed (19). Therefore, to further evaluate the role of autophagy targeting the Atg7 transcript or a scrambled (Scr) shRNA. Levels in PNPLA3 degradation, we used two alternative inhibitors of of ATG7 protein were effectively reduced in mice treated with the pathway. the Atg7-targeted shRNA (Fig. 2, Middle). Comparable inhibi- First, we treated transgenic mice expressing either PNPLA3(WT) tion of autophagy was confirmed by analysis of p62, which in- or PNPLA3(148M) with chloroquine (25 mg/kg) for 3 h (20) (Fig. −/− WT creased to a similar extent in the Pnpla3 and WT mice. In WT 1A, Upper). In PNPLA3Tg mice, chloroquine treatment increased animals, Atg7 knockdown (KD) was associated with a threefold PNPLA3 levels on LDs ∼20-fold compared with vehicle control. increase in PNPLA3 levels on hepatic LDs (Fig. 2, Top). Hepatic The changes in PNPLA3 protein levels were not associated with TG content was also increased in the WT mice, but not in the − − changes in PNPLA3 mRNA levels (Fig. 1B). In contrast to mice Pnpla3 / mice (Fig. 2, Bottom). Thus, inhibition of autophagy expressing the WT transgene, chloroquine treatment had no effect increased both the levels of PNPLA3 and TGs on hepatic LDs. on PNPLA3 levels in PNPLA3Tg148M mice. As a positive control for Moreover, the development of steatosis in association with in- chloroquine-mediated inhibition of autophagy, we monitored levels activation of autophagy was dependent on expression of PNPLA3, − − of sequestosome 1 (SQSTM1)/p62, an autophagy substrate (21). since it did not occur in the Pnpla3 / mice. If the increase in hepatic TGs in this experiment is a conse- quence of accumulation of PNPLA3 on LDs, why was steatosis seen in mice treated with Atg7 KD but not in those treated with chloroquine (Fig.
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