Welcome to the EAS 2022 Interactive Program
The congress will officially run on CET time zone (Central European Time, Milano)
Does the location of ectopic fat matter for CVD risk
Diabetes care: Changing the focus from treat to target to treat to benefit
GENETIC RISK OF FATTY LIVER DISEASE AND MORTALITY IN THE GENERAL POPULATION
Abstract
Background and Aims
Fatty liver disease associates with increased mortality. This study aims to use genetic variants implicated in fatty liver disease to assess if fatty liver disease per se causes increased mortality.
Methods
We included participants from two prospective studies of the general Danish population, the Copenhagen City Heart Study and the Copenhagen General Population Study, totaling n=110,913. All participants were genotyped for six variants with known effects on fatty liver disease: PNPLA3 rs738409, TM6SF2 rs58542926, HSD17B13 rs72613567, MBOAT7 rs641738, MTARC1 rs2642438, and GCKR rs1260326. Hazard ratios were calculated using Cox-regression.
Results
During a median follow-up of 9.5 years, 16,119 individuals died, hereof 201 due to liver-related causes, 1,736 to ischemic heart disease (IHD), and 4,973 to extrahepatic cancer. The variants at PNPLA3, HSD17B13, TM6SF2, and MBOAT7 (but not those at MTARC1 and GCKR) associated with liver-related mortality with per-allele hazard ratios of 1.3 to 1.6 (p-values<0.06). The strongest effect was seen for the PNPLA3-variant, for which homozygous carriers had a three-fold higher risk of liver-related death compared to non-carriers. A genetic risk score comprised of the variants at PNPLA3, TM6SF2 and HSD17B13 was associated with stepwise increased liver-related mortality, with a maximum hazard ratio of 13 (95% CI: 3.8-48) for those with 5 or 6 versus 0 risk-increasing alleles (Figure, bottom, p-trend=9x10E-7). The fatty liver disease variants, individually or combined, did not associate with IHD-related, extrahepatic cancer-related, or all-cause mortality (Figure, top).
Conclusions
Genetic risk of fatty liver disease associated with liver-related but not IHD-related, extrahepatic cancer-related or overall mortality in the general population.
IMPACT OF NON-ALCOHOLIC FATTY LIVER DISEASE ON CORONARY ARTERY DISEASE: A MENDELIAN RANDOMIZATION STUDY
Abstract
Background and Aims
Epidemiological studies have demonstrated an important association between non-alcoholic fatty liver disease (NAFLD) and coronary artery disease (CAD). However, it is still uncertain whether the relationship between NAFLD and CAD is causal. Our goal is to investigate the possibility of a cause-effect relationship between NAFLD and CAD.
Methods
We performed Mendelian randomization (MR) analyses using 55 independent genetic variants strongly associated with NAFLD identified in participants of the Million Veteran Program (90,408 NAFLD cases and 128,817 controls) of European ancestry. Genome-wide association study summary statistics for CAD were obtained from the CARDIoGRAMplusC4D consortium and UK Biobank (122,733 CAD cases and 424,528 controls) meta-analysis. The NAFLD variants were separated into groups according to the direction of their effects on CAD by the MR-Clust algorithm (negative, null, and positive).
Results
Traditional MR analysis does not indicate a causal association between NAFLD and CAD (OR [95% CI] = 1.05 [0.97-1.13], p = 0.274). The MR of each group individually (negative, null, and positive) shows that each group has a different effect on CAD and that the positive group is most strongly associated with CAD (OR [95% CI] = 1.53 [1.39-1.67], p = 6.49e-20). Additional MR analyses suggest that the positive group of NAFLD (variants whose effect on NAFLD is proportional to the effect on CAD) is predominantly associated with low-density lipoprotein cholesterol concentrations.
Conclusions
Our results suggest that the relationship between NAFLD and CAD is not causal and therapeutic agents targeting NAFLD may not affect CAD, unless they concomitantly decrease atherogenic blood lipoproteins concentrations.
LOW PRODUCTION OF 12Α-HYDROXYLATED BILE ACIDS PREVENTS HEPATIC STEATOSIS IN MICE WITH A HUMAN-LIKE BILE ACID POOL BY REDUCING FAT ABSORPTION
Abstract
Background and Aims
Atherosclerotic cardiovascular disease (CVD) has been associated with non-alcoholic fatty liver disease (NAFLD). Bile acids (BAs) play important roles in cholesterol and lipid metabolism, coordinating major CVD risk factors. We generated Cyp2c70-/- mice with a human-like BA composition lacking mouse-specific muricholic acids (MCAs) to accelerate translation from mice to humans. We employed this model to investigate the links between BAs and CVD risk factors.
Methods
Male and female Cyp2c70-/- mice and wild-type (WT) littermates were challenged with a 12-week Western-type high-fat diet (WTD) supplemented with 0.25% cholesterol.
Results
Cyp2c70-deficiency induced a hydrophobic BA pool with high abundances of chenodeoxycholic acid, particularly in females, due to sex-dependent suppression of sterol 12α-hydroxylase (Cyp8b1). Plasma transaminases were elevated and hepatic fibrosis was present in Cyp2c70-/- mice, especially in females. Surprisingly, female Cyp2c70-/- mice were resistant to WTD-induced obesity and hepatic steatosis while male Cyp2c70-/- mice showed similar adiposity and moderately reduced steatosis compared to WT controls. Both intestinal cholesterol and fatty acid absorption were reduced in Cyp2c70-/- mice, the latter more strongly in females, despite unaffected biliary BA secretion rates. Intriguingly, the biliary ratio 12α-/non-12α-hydroxylated BAs significantly correlated with fatty acid absorption and hepatic triglyceride.
Conclusions
The hydrophobic human-like BA pool in Cyp2c70-/- mice prevents WTD-induced obesity in female mice and NAFLD development in both genders, primarily due to impaired intestinal fat absorption. Our data point to a key role for 12α-hydroxylated BAs in control of intestinal fat absorption. Our human-like mice model represents a unique model to establish the interconnections between BAs and CVD risks.
DE NOVO LIPOGENESIS MEDIATES BENEFICIAL EFFECTS OF ISOENERGETIC DIETARY INTERVENTIONS ON FATTY LIVER: INSIGHTS FROM THE MEDEA RANDOMIZED CLINICAL TRIAL.
Abstract
Background and Aims
Fatty liver (FL) is a consequence of the imbalance between hepatic lipid storage, disposal, and partitioning. A Multifactorial-diet high in fiber, monounsaturated fatty acids (MUFA), n-6 and n-3 polyunsaturated fatty acids, polyphenols, and vitamins compared with a MUFA rich-diet, reduces FL in people with type 2 diabetes (T2D) by 40%. We evaluated whether dietary effects on LF were mediated by changes in hepatic De Novo Lipogenesis (DNL), stearoyl-CoA desaturase (SCD1) activity, or β-oxidation.
Methods
According to a parallel group design, 37 patients with T2D, were randomly assigned to an 8-week isocaloric intervention with a MUFA-diet (n=20) or a Multifactorial-diet (n=17). Before and after the intervention, LF content was evaluated by 1H-MRS, fatty acids composition of serum triglycerides was measured by gas-chromatography, plasma β-hydroxybutyrate by enzymatic method. DNL and SCD-1 activity were assessed by palmitic acid/linoleic acid (C16:0/C18:2 n6) and palmitoleic acid/palmitic acid (C16:1/C16:0) ratios, respectively.
Results
DNL significantly decreased after the Multifactorial-diet (2.1±0.8 vs. 1.5±0.5; p=0.001), while did not change after the MUFA-diet (1.9±1.1 vs. 1.9±0.9; p=0.871), with a significant difference between diets (p=0.003). SCD-1 activity decreased significantly after the Multifactorial-diet (0.13±0.04 vs 0.10±0.03; p=0.004), and not significantly after the MUFA-diet (0.13±0.06 vs. 0.11±0.05; p=0.078), with no significant difference between diets (p=0.707). Fasting plasma β-hydroxybutyrate concentrations did not change after both diets. Changes in DNL index significantly and positively correlated with changes in liver fat (r=0.426; p=0.009).
Conclusions
The inhibition of DNL plays a relevant role in the reduction of fatty liver obtained with a diet rich in multiple beneficial components.
HIGH ANTIBODY TITERS AGAINST APOLIPOPROTEIN-A1 IN NAFLD: A POSSIBLE LINK BETWEEN FATTY LIVER DISEASE AND CVD ?
Abstract
Background and Aims
Non-Alcoholic Fatty Liver Disease (NAFLD) represents an increasing cause of liver disease worldwide. Cardiovascular disease is the leading cause of morbidity and mortality in these patients. Although NAFLD pathophysiology is not fully understood alterations in fat metabolism seem to play a role. Autoantibodies against apolipoprotein A-1 (AAA1) are a novel cardiovascular risk factor with a metabolic role and a function as a disruptor of the cholesterol pathway. This study aims at evaluating a possible role of anti-apoA-1 IgG in NAFLD.
Methods
Sera from 137 NAFLD patients were tested for AAA1 prevalence. Protein expression was assessed in the human hepatic cell line HepaRG by western blot analysis. Bodipy and Oil Red O staining were used to evaluate lipid content in hepatocytes and liver sections from ApoE-/- mice respectively.
Results
Elevated AAA1 seropositivity was found in patients with NAFLD (46%). In vitro, AAA1 induced lipid accumulation in hepatocytes (5.9 vs 2.5, p=0.0008) and this lipid overload was associated with a high SREBP1 but not SREBP2 expression. AAA1 caused a significant TLR2-mediated increase of the proinflammatory cytokines IL-6 (680 vs. 163 pg/mL, P=0.03), TNF-a (391 vs 266 pg/mL, P=0.04) and IL-8 (174.1 vs. 72.6 ng/mL, P=0.03) detected in hepatocyte supernatants. In vivo, AAA1 induced higher lipid accumulation in the livers of ApoE-/- mice (1.23 vs 0.53, p=0.03).
Conclusions
Anti-apoA-1 IgG are frequent in NAFLD, cause a strong inflammatory response and promote lipid accumulation in human hepatocytes and mice. We hypothesize that AAA1 may be a potential contributor in the development of NAFLD.