Biology subjects

Jauhiainen, M.

Publications and source records attributed to Jauhiainen, M..

6 recordsLinked to original sources

bioRxiv2022

Kupffer cells dictate hepatic responses to the atherogenic dyslipidemic insult

Apolipoprotein-B (APOB) containing lipoproteins are causative for atherosclerotic cardiovascular disease. Whether the vasculature is the initial responding site or if atherogenic-dyslipidemia effects other organs simultaneously is unknown. We set out to discover how the liver responds to a dyslipidemic insult through the creation of inducible mouse models based on human familial hypercholesterolemia mutations and in vivo tracing of APOB. An acute transition to atherogenic APOB-lipoprotein plasma levels resulted in rapid accumulation of triglycerides and cholesterol in the liver. Single cell RNA-seq and flow cytometry disclosed that multiple immune cells have the ability to engulf APOB-lipoproteins. However bulk RNA-seq of the liver revealed an inflammatory Kupffer cell-specific transcriptional program that could not be activated by a western diet alone. Depletion of Kupffer cells through clodronate liposomes or CD8 T cell targeting rapidly raised plasma lipoprotein levels, indicating that these liver macrophages help restrain and buffer atherogenic lipoproteins, whilst simultaneously secreting pro-atherosclerotic factors into plasma. Our results place Kupffer cells as a key gateway in organizing systemic responses at the initiation of atherosclerosis.

immunology↗

bioRxiv2021

The HDL particle composition determines its anti-tumor activity in pancreatic cancer

Despite significant efforts in the last years to improve therapeutic options, pancreatic cancer remains a fatal disease and is expected to become the second leading cause of cancer-related deaths in the next decade. Late diagnosis and a complex, fibrotic tumor microenvironment produces a therapeutically hardly approachable situation with rapidly emerging resistance mechanisms. In response to this hostile microenvironment, previous research identified lipid metabolic pathways to be highly enriched in pancreatic ductal adenocarcinoma (PDAC) cells. Thereby, cholesterol uptake and synthesis was shown to promote a growth advantage to, and chemotherapy resistance for PDAC tumor cells. Here, we demonstrate that efficient, net-cholesterol removal from cancer cells, driven by high-density lipoprotein (HDL) mediated efflux, results in a significant PDAC cell growth reduction, apoptosis and a decreased PDAC tumor development in vivo. This effect is driven by an HDL particle composition-dependent interaction with SR-B1 and ABCA1 on cancer cells, two major lipid flux receptors, which differentially regulate cholesterol transport at the plasma membrane. Eventually, we show that pancreatic cancer patients display reduced plasma levels of HDL-cholesterol, directly translating into a reduced cholesterol efflux capacity of patient-derived plasma samples. We conclude that cholesterol depletion from PDAC cells, together with possible interventions that shunt the import and endogenous synthesis pathways of cholesterol, might represent a promising strategy to increase and complement the currently available treatment options to improve the prognosis of patients suffering from PDAC.

cancer biology↗

bioRxiv2020

Alternate models of acute dyslipidemia reveal divergent pathways upon atherosclerosis initiation

Atherosclerosis is thought to be initiated by the sub-intimal retention of apolipoprotein-B containing lipoproteins within susceptible sites of the vasculature. Understanding this initiation is not possible with current legacy mouse models of atherosclerosis. We created two mouse strains of inducible hypercholesterolemia based on conditional loss of apolipoprotein E or through inducible expression of a gain-of-function proprotein convertase subtilisin/kexin type 9 D374Y mutation. Both strains rapidly broke plasma-lipid homeostasis and converted to a state of atherogenic dyslipidemia, resulting in overt aortic-accumulation of lipoproteins within 10 days. RNA-sequencing revealed that the vascular response is completely dependent on the route taken to dyslipidemia, which nevertheless implicates known pathogenic pathways in the aetiology of atherosclerosis, and further implicates APOE as an inhibitor of inflammation. As atherosclerosis develops, a convergence of common mechanistic processes emerge in both strains with significant involvement of the immune system, and targeting of CD8 T cells can regulate a conserved aortic response. Our results define atherosclerosis initiation as highly heterogeneous process and identify multiple potential therapeutic targets that may influence disease onset.

physiology↗

bioRxiv2018

Genetics of human plasma lipidome: Understanding lipid metabolism and its link to diseases beyond traditional lipids

AimGenetic investigation of human plasma lipidome to get insights into lipid-related disorders beyond traditional lipid measures.\n\nMethods and ResultsWe performed a genome-wide association study (GWAS) of 141 lipid species (n=2,181 individuals), followed by phenome-wide scans (PheWAS) with 44 clinical endpoints related to cardiometabolic, psychiatric and gastrointestinal disorders (n=456,941 individuals). SNP-based heritability for lipid species ranged from 0.10-0.54. Lipids with long-chain polyunsaturated fatty acids showed higher heritability and genetic sharing, suggesting considerable genetic regulation at acyl chains levels. We identified 35 genomic regions associated with at least one lipid species (P<5x10-8), revealing 37 new SNP-lipid species pair associations e.g. new association between ABCG5/8 and CE(20:2;0). PheWAS of lipid-species-associated loci suggested new associations of BLK with obesity, FADS2 with thrombophlebitis, and BLK and SPTLC3 with gallbladder disease (false discovery rate <0.05). The association patterns of lipid-species-associated loci supplied clues to their probable roles in lipid metabolism e.g. suggestive role of SYNGR1, MIR100HG, and PTPRN2 in desaturation and/or elongation of fatty acids. At known lipid loci (FADS2, APOA5 and LPL), genetic associations provided detailed insights to their roles in lipid biology and diseases. We also show that traditional lipid measures may fail to capture lipids such as lysophospatidylcholines (LPCs) and phosphatidylcholines (PCs) that are potential disease risk factors, but are not included in routine screens. The full genome-wide association statistics are available on the web-based database (http://35.205.141.92).\n\nConclusionOur study reveals genetic regulation of plasma lipidome and highlights the potential of lipidomic profiling in disease gene mapping.

genetics↗

bioRxiv2018

Metabolomic signature of angiopoietin-like protein 3 deficiency in fasting and postprandial state

ObjectiveLoss-of-function variants in the angiopoietin-like 3 gene (ANGPTL3) have been associated with low levels of plasma lipoproteins and decreased coronary artery disease risk. We aimed to determine detailed metabolic effects of genetically-induced ANGPTL3 deficiency in fasting and postprandial state.\n\nApproach and ResultsWe studied individuals carrying S17X loss-of-function mutation in ANGPTL3 (6 homozygous and 32 heterozygous carriers) and 38 noncarriers. Nuclear magnetic resonance metabolomics was used to quantify 225 circulating metabolic measures. We compared metabolic differences between loss-of-function carriers and noncarriers in fasting state and after a high fat meal. In fasting, ANGPTL3 deficiency was characterized by similar extent of reductions in low-density lipoprotein cholesterol (0.74 SD-units lower concentration per loss-of-function allele [95%CI 0.42-1.06]) as observed for many triglyceride-rich lipoprotein measures, including very-low-density lipoprotein cholesterol (0.75 [0.45-1.05]). Within most lipoprotein subclasses, absolute levels of cholesterol were decreased more than triglycerides, resulting in the relative proportion of cholesterol being reduced within triglyceride-rich lipoproteins and their remnants. Further, beta-hydroxybutyrate was elevated (0.55 [0.21-0.89]). Homozygous ANGPTL3 loss-of-function carriers showed essentially no postprandial increase in triglyceride-rich lipoproteins and fatty acids, without evidence for adverse compensatory metabolic effects.\n\nConclusionsIn addition to overall triglyceride and low-density lipoprotein cholesterol lowering effects, ANGPTL3 deficiency results in reduction of cholesterol proportion within triglyceride-rich lipoproteins and their remnants. Further, ANGPTL3 loss-of-function carriers had elevated ketone body production, suggesting enhanced hepatic fatty acid beta-oxidation. The detailed metabolic profile in human knockouts of ANGPTL3 reinforces inactivation of ANGPTL3 as a promising therapeutic target for decreasing cardiovascular risk.\n\nHIGHLIGHTSO_LIANGPTL3 deficiency results in similar reductions in LDL cholesterol and many triglyceride-rich lipoprotein lipids measures, such as VLDL cholesterol, with no evidence of substantial adverse effects on the comprehensive panel of circulating metabolite biomarkers tested here.\nC_LIO_LIIn particular, ANGPTL3 deficiency results in reduction of cholesterol content in triglyceride-rich lipoproteins and their remnants, which have been highlighted as risk factor for cardiovascular disease independently of LDL levels.\nC_LIO_LIHomozygous ANGPTL3 loss-of-function carriers show essentially no postprandial increase in triglyceride-rich lipoproteins and fatty acids in response to a fat challenge, and display consistently elevated postprandial levels of ketone bodies and lactate when compared to noncarriers, suggesting enhanced hepatic fatty acid beta-oxidation.\nC_LI

genetics↗

bioRxiv2018

Coronary artery disease risk and lipidomic profiles are similar in familial and population-ascertained hyperlipidemias

Aims: To characterize and compare coronary artery disease (CAD) risk and detailed lipidomic profiles of individuals with familial and population-ascertained hyperlipidemias.\n\nMethods and Results: We determined incident CAD risk for 760 members of 66 hyperlipidemic families ([≥] 2 first degree relatives with the same hyperlipidemia) and 19,644 Finnish FINRISK population study participants. We also quantified 151 lipid species in plasma or serum samples from 550 members of 73 hyperlipidemic pedigrees and 897 FINRISK participants using a mass spectrometric shotgun lipidomics platform. Hyperlipidemias (LDL-C or triacylglycerides over 90th population percentile) were associated with increased CAD risk (high LDL-C: HR 1.74, 95% CI 1.48-2.04; high triacylglycerides: HR 1.38, 95% CI 1.09-1.74) and the risk estimates were very similar between the family and population samples. High LDL-C was associated with altered levels of 105 lipid species in families (p-value range 0.033-7.3*10-20 at 5% false discovery rate) and 51 species in the population samples (p-value range 0.017-6.8*10-21). Hypertriglyceridemia was associated with altered levels of 117 lipid species in families (p-value range 0.035-1.8*10-49) and 119 species in the population sample (p-value range 0.038-2.3*10-56). The lipidomics profiles of hyperlipidemias were highly similar in families and population samples.\n\nConclusion: We identified distinct lipidomic profiles associated with high LDL-C and triacylglyceride levels. CAD risk, lipidomic profiles and genetic profiles are highly similar between familial and population-ascertained hyperlipidemias, providing evidence of similar and overlapping underlying mechanisms. Our results do not support different screening and treatment for such hyperlipidemias.

epidemiology↗