The PNPLA3 I148M variant and chronic liver disease : When a genetic mutation meets nutrients

Abstract The isoleucine to methionine substitution at position 148 in the patatin-like phospholipase domain containing 3 protein (PNPLA3; I148M variant, rs738409) is associated with liver fat accumulation and an increased risk of chronic liver disease ranging from hepatitis to hepatocellular carcinoma. This review discusses the interaction between the PNPLA3 I148M variant and obesity/intake of specific nutrients in determining the susceptibility to liver disease. We present the results of several studies showing that obesity or alcohol abuse enhances the effect of the PNPLA3 I148M variant on the liver. We also show that specific nutrients interact with the PNPLA3 I148M variant in modulating liver disease susceptibility

PNPLA 3 I148M genetic variant associates with insulin resistance and baseline viral load in HCV genotype 2 but not in genotype 3 infection

Peer reviewe

Molecular genetics of patatin-like phospholipase domain-containing 3 and chronic liver disease

Chronic liver disease is a major health burden worldwide. Major determinants of this condition are viral infections, alcohol abuse and obesity. Genetic background modulates the effect of damaging agents on the liver. The genetic variant rs738409 in the patatin-like phospholipase domain-containing 3 (PNPLA3) gene associates with increased susceptibility to the entire spectrum of chronic liver disease, and in particular with non-alcoholic fatty liver disease. The variant results in an isoleucine to methionine substitution at position 148 (I148M) of the amino acidic sequence and was first associated with increased hepatocyte fat content. Despite the strength of the genetic association, the mechanisms causing liver fat accumulation and hepatocyte damage are not yet understood. In this thesis, we tested the following hypotheses: 1) PNPLA3 is involved in hepatic very low density lipoprotein secretion 2) the protein acts as a glycerolipid hydrolase and the 148M mutation is a loss of function 3) PNPLA3 has a specific role in retinol metabolism in hepatic stellate cells. We tested the first hypothesis measuring VLDL secretion in a cohort of 55 individuals genotyped for the I148M variant and we found that carriers of the 148M allele secret less VLDL for a given amount of liver fat. We confirmed this result in vitro by measuring APOB secretion in cell lines stably overexpressing the 148I or the 148M PNPLA3. We tested the second hypothesis performing enzymatic activity assays using purified 148I and 148M recombinant proteins. The wild type protein had glycerolipid hydrolase activity and the 148M mutation induced a loss of function. Finally, we tested the third hypothesis assessing the effect of PNPLA3 up- and down-regulation on hepatic stellate cell retinyl palmitate content and retinol release. We found that PNPLA3 insulin–mediated up-regulation induces retinol release from hepatic stellate cells and that this effect is abolished by PNPLA3 silencing. We confirmed this finding by looking at human circulating levels of RBP4, a reliable marker of retinol plasma levels, in 146 individuals genotyped for the I148M variant. We found carriers of the M allele to have lower RBP4 plasma levels, confirming the role of PNPLA3 in retinol metabolism. In conclusion, we identified two possible mechanisms underlying the susceptibility to chronic liver disease in carriers of the PNPLA3 mutation: 1) reduced intracellular triglyceride mobilization leading to hepatocyte damage 2) impaired hepatic stellate cell retinol metabolism causing abnormal response of hepatocytes to damaging agents

Effects of Bilberry and Oat intake on lipids, inflammation and exercise capacity after Acute Myocardial Infarction (BIOAMI): study protocol for a randomized, double-blind, placebo-controlled trial

Background: Bilberries from Sweden, rich in polyphenols, have shown cholesterol-lowering effects in small studies, and the cholesterol-lowering properties of oats, with abundant beta-glucans and potentially bioactive phytochemicals, are well established. Both may provide cardiometabolic benefits following acute myocardial infarction (AMI), but large studies of adequate statistical power and appropriate duration are needed to confirm clinically relevant treatment effects. No previous study has evaluated the potential additive or synergistic effects of bilberry combined with oats on cardiometabolic risk factors. Our primary objective is to assess cardioprotective effects of diet supplementation with dried bilberry or with bioprocessed oat bran, with a secondary explorative objective of assessing their combination, compared with a neutral isocaloric reference supplement, initiated within 5 days following percutaneous coronary intervention (PCI) for AMI. Methods: The effects of Bilberry and Oat intake on lipids, inflammation and exercise capacity after Acute Myocardial Infarction (BIOAMI) trial is a double-blind, randomized, placebo-controlled clinical trial. A total of 900 patients will be randomized post-PCI to one of four dietary intervention arms. After randomization, subjects will receive beverages with bilberry powder (active), beverages with high-fiber bioprocessed oat bran (active), beverages with bilberry and oats combined (active), or reference beverages containing no active bilberry or active oats, for consumption twice daily during a 3-month intervention. The primary endpoint is the difference in LDL cholesterol change between the intervention groups after 3 months. The major secondary endpoint is exercise capacity at 3 months. Other secondary endpoints include plasma concentrations of biochemical markers of inflammation, metabolomics, and gut microbiota composition after 3 months. Discussion: Controlling hyperlipidemia and inflammation is critical to preventing new cardiovascular events, but novel pharmacological treatments for these conditions are expensive and associated with negative side effects. If bilberry and/or oat, in addition to standard medical therapy, can lower LDL cholesterol and inflammation more than standard therapy alone, this could be a cost-effective and safe dietary strategy for secondary prevention after AMI. Trial registration: ClinicalTrials.gov NCT03620266. Registered on August 8, 2018

<it>PNPLA 3</it> I148M genetic variant associates with insulin resistance and baseline viral load in HCV genotype 2 but not in genotype 3 infection

Abstract Background Hepatic steatosis in HCV patients has been postulated as a risk factor associated with a higher frequency of fibrosis and cirrhosis. A single genetic variant, PNPLA3 I148M, has been widely associated with increased hepatic steatosis. Previous studies of the PNPLA3 I148M sequence variant in HCV infected individuals have reported an association between this variant and prevalence of steatosis, fibrosis, and cirrhosis. To evaluate the impact of PNPLA3 I148M variant on metabolic traits and treatment response in HCV genotype 2 and 3 infected patients. Methods Three hundred and eighty-two treatment naïve HCV genotype 2 or 3 infected patients were included in a phase III, open label, randomized, multicenter, investigator-initiated trial (the NORDynamIC study), in which pretreatment liver biopsies were mandatory. PNPLA3I148M genotyping was performed in a total of 359 Caucasian patients. Results In HCV genotype 2 infected patients carrying the PNPLA3 148M allele, there was significantly increased insulin resistance (P = 0.023) and lower viral load (P = 0.005) at baseline as well as the first seven days of antiviral treatment. These results were not observed in HCV genotype 3 infected patients. Conclusions Our results suggest a possible association between the PNPLA3 148M allele and insulin resistance as well as baseline viral load in HCV genotype 2, but not in genotype 3.</p

Temporal electrocardiographic changes in anterior ST elevation myocardial infarction versus the Takotsubo syndrome

Background: Electrocardiography (ECG) on admission is similar in ST elevation myocardial infarction (STEMI) and Takotsubo syndrome (TTS). ECG on admission has been extensively investigated and compared between STEMI and TTS, however, only a few studies have compared temporal ECG. Our aim was to compare ECG in anterior STEMI versus female TTS from admission to day 30. Methods: Adult patients with anterior STEMI or TTS treated at Sahlgrenska University Hospital (Gothenburg, Sweden) from December 2019 to June 2022 were prospectively enrolled. Baseline characteristics, clinical variables and ECGs from admission to day 30 were analyzed. Using a mixed effects model, we compared temporal ECG between female patients with anterior STEMI or TTS, as well as between female and male patients with anterior STEMI. Results: A total of 101 anterior STEMI patients (31 female, 70 male) and 34 TTS patients (29 female, 5 male) were included. The temporal pattern of T wave inversion was similar between female anterior STEMI and female TTS, as well as between female and male anterior STEMI. ST elevation was more common, whereas QT prolongation was less common, in anterior STEMI compared with TTS. Q wave pathology was more similar between female anterior STEMI and female TTS than between female and male anterior STEMI. Conclusions: The pattern of T wave inversion and Q wave pathology from admission to day 30 was similar in female patients with anterior STEMI and female patients with TTS. Temporal ECG in female patients with TTS may be interpreted as following a “transient ischemic” pattern