Nonalcoholic fatty liver disease (NAFLD) is a burgeoning health problem that affects one-third of adults and an increasing number of children in the U.S. The disease process begins with the accumulation of triglyceride (TG) in the liver (steatosis), which in some individuals elicits an inflammatory response (steatohepatitis) that can progress to cirrhosis, and possibly liver cancer. Although various factors (e.g., obesity, insulin resistance) are associated with NAFLD in cross-sectional studies, the pathogenesis of NAFLD remains poorly understood and therapeutic options are currently very limited. Our group has taken a genetic approach to identify causal factors that contribute to NAFLD. Recently, we identified a missense mutation (I148M) in patatin-like phospholipase domain-containing protein, PNPLA3 that is strongly associated with both hepatic TG content and hepatic injury. The variant is most common in Hispanics, the group with the greatest prevalence of hepatic steatosis and least common in African-Americans who have the lowest frequency of steatosis. Subsequent studies have confirmed our findings and showed that the PNPLA3-I148M variant is enriched in subjects with biopsy-proven steatohepatitis and with alcohol-related cirrhosis. Thus, PNPLA3 is implicated as a contributing factor in the full spectrum of NAFLD as well as alcoholic cirrhosis. Basic questions remain regarding the physiological role of PNPLA3 and how genetic variation in this enzyme promotes hepatic TG accumulation, inflammation and fibrosis. The overall goal of this application is to elucidate the role of PNPLA3 in fatty liver disease. To this end, we will use a combination of classical biochemistry and physiology plus state-of-the-art mass-spectrometry in mice with genetically-defined changes in PNPLA3 function to identify the substrates and products of the enzyme, the role in PNPLA3 in lipid metabolism and the molecular basis for its association with TG accumulation and liver damage. Two complementary approaches will be used to identify the biological substrate(s) of PNPLA3: i) a candidate substrate approach using purified enzyme (Aim 1a) and a comparative lipidomic approach in genetically- modified mice (Aim 1b) to identify lipids that are altered by changes in PNPLA3 activity.
In Aims 2 we will use our mouse models to examine effects of PNPLA3-I148M on hepatic lipid metabolism.
Aim 3 focuses on identifying molecular mechanisms by which PNPLA3-I148M promotes TG accumulation in the liver. Finally, in Aim 4 we will establish a mouse model in which to investigate the mechanisms by which PNPLA3 contributes to hepatic inflammation and fibrosis. By elucidating the biological role of PNPLA3 and the mechanisms by which the I148M mutation confers susceptibility to fatty liver disease, the experiments outlined in this proposal will provide new insight into the pathogenesis of a major human disease that continues to increase in prevalence. Our ultimate goal is to develop new approaches and strategies to diagnose, prevent and treat NAFLD.

Public Health Relevance

Nonalcoholic fatty liver disease (NAFLD) is a burgeoning health problem that affects one-third of adults and an increasing number of children in the United States. Insights into the causes of NAFLD are urgently required since no therapeutic intervention has proven to be uniformly effective in this disease. We have used human genetic studies to identify a protein that contributes to fatty liver disease, and will exploit this finding to elucidate the underlying causes of the condition. Our ultimate goal will be to develop new approaches and strategies to diagnose, prevent and treat NAFLD.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Special Emphasis Panel (ZRG1-DKUS-B (03))
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Doo, Edward
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University of Texas Sw Medical Center Dallas
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United States
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Mitsche, Matthew A; Hobbs, Helen H; Cohen, Jonathan C (2018) Patatin-like phospholipase domain-containing protein 3 promotes transfer of essential fatty acids from triglycerides to phospholipids in hepatic lipid droplets. J Biol Chem 293:6958-6968
Hobbs, Helen H (2018) Science, serendipity, and the single degree. J Clin Invest 128:4218-4223
Stender, Stefan; Smagris, Eriks; Lauridsen, Bo K et al. (2018) Relationship between genetic variation at PPP1R3B and levels of liver glycogen and triglyceride. Hepatology 67:2182-2195
BasuRay, Soumik; Smagris, Eriks; Cohen, Jonathan C et al. (2017) The PNPLA3 variant associated with fatty liver disease (I148M) accumulates on lipid droplets by evading ubiquitylation. Hepatology 66:1111-1124
Stender, Stefan; Kozlitina, Julia; Nordestgaard, Børge G et al. (2017) Adiposity amplifies the genetic risk of fatty liver disease conferred by multiple loci. Nat Genet 49:842-847
Smagris, Eriks; Gilyard, Shenise; BasuRay, Soumik et al. (2016) Inactivation of Tm6sf2, a Gene Defective in Fatty Liver Disease, Impairs Lipidation but Not Secretion of Very Low Density Lipoproteins. J Biol Chem 291:10659-76
Smagris, Eriks; BasuRay, Soumik; Li, John et al. (2015) Pnpla3I148M knockin mice accumulate PNPLA3 on lipid droplets and develop hepatic steatosis. Hepatology 61:108-18
Stender, Stefan; Chakrabarti, Rima S; Xing, Chao et al. (2015) Adult-onset liver disease and hepatocellular carcinoma in S-adenosylhomocysteine hydrolase deficiency. Mol Genet Metab 116:269-74
Wang, Yan; Gusarova, Viktoria; Banfi, Serena et al. (2015) Inactivation of ANGPTL3 reduces hepatic VLDL-triglyceride secretion. J Lipid Res 56:1296-307
Kozlitina, Julia; Smagris, Eriks; Stender, Stefan et al. (2014) Exome-wide association study identifies a TM6SF2 variant that confers susceptibility to nonalcoholic fatty liver disease. Nat Genet 46:352-6

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