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Four-Week Omega-3 Supplementation in Carriers of the Prosteatotic PNPLA3 p.I148M Genetic Variant: An Open-Label Study.
Kuttner, CS, Mancina, R, Wagenpfeil, G, Lammert, F, Stokes, CS
Lifestyle genomics. 2019;(1-6):10-17
Abstract
BACKGROUND/AIMS: The PNPLA3 loss-of-function variant p.I148M is a strong genetic determinant of nonalcoholic fatty liver disease. The PNPLA3 protein functions as an intracellular lipase in the liver, with a greater activity on unsaturated fatty acids. This study aimed to determine whether short-term supplementation with omega-3 fatty acids impacts hepatic steatosis differently in PNPLA3 p.148I wild-type individuals as compared to homozygous carriers of the PNPLA3 p.148M variant. METHODS Twenty subjects with hepatic steatosis (50% women, age 18-77 years) were included. Ten subjects homozygous for the PNPLA3 148M variant were matched to 10 wild-type individuals. The subjects received 4 g omega-3 fatty acids (1,840 mg eicosapentaenoic acid and 1,520 mg docosahexaenoic acid) a day for 4 weeks. Transient elastography with a controlled attenuation parameter (CAP) was used to quantify liver fat before and after the intervention. Body composition, fibrosis, liver function tests, serum free fatty acids (FFA) and glucose markers were compared. RESULTS Patients homozygous for the PNPLA3 p.148M variant (risk group) demonstrated no significant changes in CAP compared to baseline (284 ± 55 vs. 287 ± 65 dB/m) as did the control group (256 ± 56 vs. 262 ± 55 dB/m). While serum liver enzyme activities remained unchanged in both groups, the risk group displayed significantly (p = 0.02) lower baseline FFA concentrations (334.5 [range 281.0-431.0] vs. 564.5 [range 509.0-682.0] μmol/L), which markedly increased by 9.1% after the intervention. In contrast, FFA concentrations decreased significantly (p = 0.01) by 28.3% in the wild-type group. CONCLUSIONS Short-term omega-3 fatty acid supplementation did not significantly alter hepatic steatosis. The nutrigenomic and metabolic effects of omega-3 fatty acids should be investigated further in carriers of the PNPLA3 148M risk variant.
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2.
The fatty acid translocase gene CD36 and lingual lipase influence oral sensitivity to fat in obese subjects.
Pepino, MY, Love-Gregory, L, Klein, S, Abumrad, NA
Journal of lipid research. 2012;(3):561-566
Abstract
The precise orosensory inputs engaged for dietary lipids detection in humans are unknown. We evaluated whether a common single nucleotide polymorphism (rs1761667) in the CD36 gene that reduces CD36 expression and the addition of orlistat, a lipase inhibitor, to reduce FA release from triacylglycerols (TGs), the main component of dietary fats, would attenuate fat orosensory sensitivity in humans. Twenty-one obese subjects with different rs1761667 genotypes (6 AA, 7 AG, and 8 GG) were studied on two occasions in which oleic acid and triolein orosensory detection thresholds were measured using emulsions prepared with and without orlistat. Subjects homozygous for the G-allele had 8-fold lower oral detection thresholds for oleic acid and triolein than subjects homozygous for the A allele, which associates with lower CD36 expression (P = 0.03). Thresholds for heterozygous subjects were intermediate. The addition of orlistat increased detection thresholds for triolein (log threshold = -0.3 ± 0.2 vs. 0.3 ± 0.1; P < 0.001) but not oleic acid (log threshold = -1.0 ± 0.2 vs. -0.8 ± 0.2; P > 0.2). In conclusion, this is the first experimental evidence for a role of CD36 in fat gustatory perception in humans. The data also support involvement of lingual lipase and are consistent with the concept that FA and not TG is the sensed stimulus.
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3.
Hepatic lipase C-480T genotype-dependent benefit from long-term hormone replacement therapy for atherosclerosis progression in postmenopausal women.
Fan, YM, Dastidar, P, Jokela, H, Punnonen, R, Lehtimäki, T
The Journal of clinical endocrinology and metabolism. 2005;(6):3786-92
Abstract
Hepatic lipase (HL) is a lipolytic enzyme that hydrolyzes triglycerides and phospholipids in almost all major classes of lipoproteins. The HL gene has a functional promoter polymorphism at position -480, which affects transcription and leads to CC, CT, and TT genotypes. We investigated the effect of long-term hormone replacement therapy (HRT) on the progression of atherosclerosis in a 5-yr follow-up observational study of 88 postmenopausal women with different HL genotypes (CC, n = 49; CT, n = 34; TT, n = 5). These women, aged 45-71 yr, were divided into three groups based on the use of HRT. The HRT-EVP group (n = 26) used sequential estradiol valerate (EV) plus progestin (levonorgestrel), the HRT-EV group used EV alone (n = 32), and the control group (n = 30) used no HRT. The HRT-EV and HRT-EVP groups started estrogen at menopause for estrogen-deficiency symptoms, whereas the control group took no estrogen due to either the absence of such symptoms or a dislike of estrogen therapy. In addition to serum lipid concentration and HL genotype, the atherosclerosis severity score (ASC) for the abdominal aorta and carotid arteries was determined by ultrasonography. There was a significant interaction between HRT therapy and HL genotypes on the increase in ASC (P = 0.046) after adjustment for age, body mass index, changes in high-density lipoprotein cholesterol and baseline ASC. In subjects with the T allele, the progression of ASC was significantly faster in the control group than the HRT group (P = 0.0006), whereas in the CC genotype, there were no significant differences in ASC progression between the control and HRT groups. Our results suggest that the beneficial effect of HRT on atherosclerosis progression was restricted to women with the T allele, in whom the progression of ASC was slower by half. These results may help us understand in greater detail the benefits and possible risks associated with HRT in atherosclerotic diseases.
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4.
Lipoprotein metabolism in subjects with hepatic lipase deficiency.
Tilly-Kiesi, M, Schaefer, EJ, Knudsen, P, Welty, FK, Dolnikowski, GG, Taskinen, MR, Lichtenstein, AH
Metabolism: clinical and experimental. 2004;(4):520-5
Abstract
A heritable deficiency of hepatic lipase (HL) provides insights into the physiologic function of HL in vivo. The metabolism of apolipoprotein B (apoB)-100 in very-low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), and low-density lipoprotein (LDL) and of apoA-I and apoA-II in high-density lipoprotein (HDL) particles lipoprotein (Lp)(AI) and Lp(AI:AII) was assessed in 2 heterozygous males for compound mutations L334F/T383M or L334F/R186H, with 18% and 22% of HL activity, respectively, compared with 6 control males. Subjects were provided with a standard Western diet for a minimum of 3 weeks. At the end of the diet period, apo kinetics was assessed using a primed-constant infusion of [5,5,5-(2)H(3)] leucine. Mean plasma triglyceride (TG) and HDL cholesterol levels were 55% and 12% higher and LDL cholesterol levels 19% lower in the HL patients than control subjects. A higher proportion of apoB-100 was in the VLDL than IDL and LDL fractions of HL patients than control subjects due to a lower VLDL apoB-100 fractional catabolic rate (FCR) (4.63 v 9.38 pools/d, respectively) and higher hepatic production rate (PR) (33.24 v 10.87 mg/kg/d). Delayed FCR of IDL (2.78 and 6.31 pools/d) and LDL (0.128 and 0.205 pools/d) and lower PR of IDL (3.67 and 6.68 mg/kd/d) and LDL 4.57 and 13.07 mg/kg/d) was observed in HL patients relative to control subjects, respectively. ApoA-I FCR (0.09 and 0.13 pools/d) and PR (4.01 and 6.50 mg/kg/d) were slower in Lp(AI:AII) particles of HL patients relative to control subjects, respectively, accounting for the somewhat higher HDL cholesterol levels. HL deficiency may result in a lipoprotein pattern associated with low heart disease risk.
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5.
[Changes in lipid profile and paraoxonase activity in obese patients as a result of orlistat treatment].
Audikovszky, M, Pados, G, Seres, I, Harangi, M, Fülöp, P, Katona, E, Winkler, G, Paragh, G
Orvosi hetilap. 2001;(50):2779-83
Abstract
257 patients from 33 centres were involved in a six-month study, the aim of which was to assess the effect of orlistat together with a diet. The authors examined how the treatment effected the anthropometrical and lipid parameters, extending the study to the aspect of paraoxonase activity in case of 25 patients. 44 patients dropped out during the study period due to the lack of sufficient diet compliance, whereas 3 patients had to stop the therapy because of the adverse event of flatus with discharge. On the average, the body mass of the patients decreased from 100.8 +/- 18.9 to 91.3 +/- 18.6 kg, i.e. by 9.5 kgs, while their BMI was reduced from 36.1 +/- 5.6 to 32.5 +/- 5.2 kg/m2 and the circumference of the waist changing from 119.1 +/- 20 to 108.3 +/- 15.1 cm, i.e. by 10.8 cms. The blood sugar level significantly decreased from 5.7 to 5.4, while the cholesterol concentration significantly dropped from 5.9 to 5.5, the triglyceride level being reduced from 2.4 to 2.1 mmol/l and blood pressure falling significantly from 136.6/86.9 to 129.9/81.6. All the above changes showed a significant decrease. However, the HDL-cholesterol level did not change. The serum paraoxonase activity significantly increased (143 +/- 49 vs 166 +/- 43 UL) along with the standardised values for HDL (PON/HDL), even compared to the control diet group. From the above results it may be concluded that orlistat tends to have an antioxidant effect.