Human PNPLA3-I148M variant increases hepatic retention of polyunsaturated fatty acids

Luukkonen, Panu K.; Nick, Auli; Hölttä‐Vuori, Maarit; Thiele, Christoph; Isokuortti, Elina; Lallukka-Brück, Susanna E.; Zhou, You; Hakkarainen, Antti; Lundbom, Nina; Peltonen, Markku; Orho‐Melander, Marju; Orešič, Matej; Hyötyläinen, Tuulia; Hodson, Leanne; Ikonen, Elina; Yki‐Järvinen, Hannele

doi:10.1172/jci.insight.127902

Cited by 117 publications

(119 citation statements)

References 37 publications

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“…Participants. A total of 10 participants were recruited among individuals who had previously participated in our metabolic studies at the Clinical Research Unit (47,53). Inclusion criteria included: 1) Age 18 to 70 y and 2) alcohol consumption <20 g/d for women and <30 g/d for men.…”

Section: Methodsmentioning

confidence: 99%

Effect of a ketogenic diet on hepatic steatosis and hepatic mitochondrial metabolism in nonalcoholic fatty liver disease

Luukkonen

Dufour

Lyu

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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Weight loss by ketogenic diet (KD) has gained popularity in management of nonalcoholic fatty liver disease (NAFLD). KD rapidly reverses NAFLD and insulin resistance despite increasing circulating nonesterified fatty acids (NEFA), the main substrate for synthesis of intrahepatic triglycerides (IHTG). To explore the underlying mechanism, we quantified hepatic mitochondrial fluxes and their regulators in humans by using positional isotopomer NMR tracer analysis. Ten overweight/obese subjects received stable isotope infusions of: [D7]glucose, [13C4]β-hydroxybutyrate and [3-13C]lactate before and after a 6-d KD. IHTG was determined by proton magnetic resonance spectroscopy (1H-MRS). The KD diet decreased IHTG by 31% in the face of a 3% decrease in body weight and decreased hepatic insulin resistance (−58%) despite an increase in NEFA concentrations (+35%). These changes were attributed to increased net hydrolysis of IHTG and partitioning of the resulting fatty acids toward ketogenesis (+232%) due to reductions in serum insulin concentrations (−53%) and hepatic citrate synthase flux (−38%), respectively. The former was attributed to decreased hepatic insulin resistance and the latter to increased hepatic mitochondrial redox state (+167%) and decreased plasma leptin (−45%) and triiodothyronine (−21%) concentrations. These data demonstrate heretofore undescribed adaptations underlying the reversal of NAFLD by KD: That is, markedly altered hepatic mitochondrial fluxes and redox state to promote ketogenesis rather than synthesis of IHTG.

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Section: Methodsmentioning

confidence: 99%

Effect of a ketogenic diet on hepatic steatosis and hepatic mitochondrial metabolism in nonalcoholic fatty liver disease

Luukkonen

Dufour

Lyu

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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166

153

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“…A number of genetic studies have identified variants associated with an increased risk of NAFLD development. Among the most frequent are PNPLA3 rs738409 I148M, which affects remodeling of fatty acid chains in liver TG [ 28 ], TM6SF2 rs58542926 E167K, which reduces hepatic VLDL secretion [ 5 ], and MBOAT7 rs641738 [ 7 ], an enzyme involved in phospholipid acyl-chain remodeling, with respective minor (risk) allele frequencies of 24%, 7%, and 43% (based on CARDIoGRAMplusC4D consortium data [ 29 ]). While these variants were identified based on MRS-screened hepatic steatosis, the impact of the PNPLA3 and TM6SF2 variants has been confirmed in histologically diagnosed NAFLD [ 30 , 31 ].…”

Section: Epidemiologymentioning

confidence: 99%

Dysregulated lipid metabolism links NAFLD to cardiovascular disease

Deprince

Haas

Staels

2020

Molecular Metabolism

314

161

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Background Non-alcoholic fatty liver disease (NAFLD) is rapidly becoming a global health problem. Cardiovascular diseases (CVD) are the most common cause of mortality in NAFLD patients. NAFLD and CVD share several common risk factors including obesity, insulin resistance, and type 2 diabetes (T2D). Atherogenic dyslipidemia, characterized by plasma hypertriglyceridemia, increased small dense low-density lipoprotein (LDL) particles, and decreased high-density lipoprotein cholesterol (HDL-C) levels, is often observed in NAFLD patients. Scope of review In this review, we highlight recent epidemiological studies evaluating the link between NAFLD and CVD risk. We further focus on recent mechanistic insights into the links between NAFLD and altered lipoprotein metabolism. We also discuss current therapeutic strategies for NAFLD and their potential impact on NAFLD-associated CVD risk. Major conclusions Alterations in hepatic lipid and lipoprotein metabolism are major contributing factors to the increased CVD risk in NAFLD patients, and many promising NASH therapies in development also improve dyslipidemia in clinical trials.

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“…PNPLA3 has intrinsic lipase activity on triglycerides, phospholipids, and retinyl esters, mediating the hydrolytic production of oleate and other unsaturated fatty acids, including arachidonic acid (21,33). While the wild-type protein is rapidly degraded, the mutant protein cannot be ubiquitylated and consequently accumulates on the LD surface, simultaneously altering core lipid remodeling and turnover (21,(34)(35)(36). The mutant I148M protein functions as a co-dominant negative rather than a loss-of-function allele, impairing LD hydrolysis (36,37).…”

Section:  Pnpla3mentioning

confidence: 99%

“…While the wild-type protein is rapidly degraded, the mutant protein cannot be ubiquitylated and consequently accumulates on the LD surface, simultaneously altering core lipid remodeling and turnover (21,(34)(35)(36). The mutant I148M protein functions as a co-dominant negative rather than a loss-of-function allele, impairing LD hydrolysis (36,37). The mechanisms for impaired LD lipolysis with the mutant PNPLA3 I148M include sequestration of the required cofactor, 1 abhydrolase domain containing 5 (ABHD5/CGI58) ( Figure 1), that normally promotes lipolysis by adipose triglyceride lipase, ATGL/PNPLA2 (38,39).…”

Section:  Pnpla3mentioning

confidence: 99%

“…protein on lipid droplets with trans-repression of ATGL (21,34,37,41), carriage of the I148M variant is also associated with an alteration of lipid remodeling with accumulation of polyunsaturated fatty acids in DAG/TAGs and depletion in phospholipids, which is accounted for by reduced enzymatic activity (34,42). Furthermore, the I148M variant impairs retinol release from hepatic stellate cells while also reducing LD abundance, a combination that promotes stellate cell activation, leading to inflammation, fibrogenesis, and carcinogenesis (33,43,44).…”

Section: Accepted Articlementioning

confidence: 99%

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Genetic Pathways in Nonalcoholic Fatty Liver Disease: Insights From Systems Biology

et al. 2020

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Nonalcoholic fatty liver disease (NAFLD) represents a burgeoning worldwide epidemic whose etiology reflects multiple interactions between environmental and genetic factors. Here, we review the major pathways and dominant genetic modifiers known to be relevant players in human NAFLD and which may determine key components of the heritability of distinctive disease traits including steatosis and fibrosis. In addition, we have employed general assumptions which are based on known genetic factors in NAFLD to build a systems biology prediction model that includes functional enrichment. This prediction model highlights additional complementary pathways that represent plausible intersecting signaling networks that we define here as an NAFLD‐Reactome. We review the evidence connecting variants in each of the major known genetic modifiers (variants in patatin‐like phospholipase domain containing 3, transmembrane 6 superfamily member 2, membrane‐bound O‐acyltransferase domain containing 7, glucokinase regulator, and hydroxysteroid 17‐beta dehydrogenase 13) to NAFLD and expand the associated underlying mechanisms using functional enrichment predictions, based on both preclinical and cell‐based experimental findings. These major candidate gene variants function in distinct pathways, including substrate delivery for de novo lipogenesis; mitochondrial energy use; lipid droplet assembly, lipolytic catabolism, and fatty acid compartmentalization; and very low‐density lipoprotein assembly and secretion. The NAFLD‐Reactome model expands these pathways and allows for hypothesis testing, as well as serving as a discovery platform for druggable targets across multiple pathways that promote NAFLD development and influence several progressive outcomes. In conclusion, we summarize the strengths and weaknesses of studies implicating selected variants in the pathophysiology of NAFLD and highlight opportunities for future clinical research and pharmacologic intervention, as well as the implications for clinical practice.

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Human PNPLA3-I148M variant increases hepatic retention of polyunsaturated fatty acids

Cited by 117 publications

References 37 publications

Effect of a ketogenic diet on hepatic steatosis and hepatic mitochondrial metabolism in nonalcoholic fatty liver disease

Effect of a ketogenic diet on hepatic steatosis and hepatic mitochondrial metabolism in nonalcoholic fatty liver disease

Dysregulated lipid metabolism links NAFLD to cardiovascular disease

Genetic Pathways in Nonalcoholic Fatty Liver Disease: Insights From Systems Biology

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