Menopausal Status and Abdominal Obesity Are Significant Determinants of Hepatic Lipid Metabolism in Women

Abstract

Background: Android fat distribution (abdominal obesity) is associated with insulin resistance, hepatic steatosis, and greater secretion of large very low-density lipoprotein (VLDL) particles in men. Since abdominal obesity is becoming increasingly prevalent in women, we aimed to investigate the relationship between android fat and hepatic lipid metabolism in pre- and postmenopausal women.

Methods and results: We used a combination of stable isotope tracer techniques to investigate intrahepatic fatty acid synthesis and partitioning in 29 lean and 29 abdominally obese women (android fat/total fat 0.065 [0.02 to 0.08] and 0.095 [0.08 to 0.11], respectively). Thirty women were premenopausal aged 35 to 45 and they were matched for abdominal obesity with 28 postmenopausal women aged 55 to 65. As anticipated, abdominal obese women were more insulin resistant with enhanced hepatic secretion of large (404±30 versus 268±26 mg/kg lean mass, P<0.001) but not small VLDL (160±11 versus 142±13). However, postmenopausal status had a pronounced effect on the characteristics of small VLDL particles, which were considerably triglyceride-enriched (production ratio of VLDL2- triglyceride:apolipoprotein B 30±5.3 versus 19±1.6, P<0.05). In contrast to postmenopausal women, there was a tight control of hepatic fatty acid metabolism and triglyceride production in premenopausal women, whereby oxidation (rs=-0.49, P=0.006), de novo lipogenesis (rs=0.55, P=0.003), and desaturation (rs=0.48, P=0.012) were closely correlated with abdominal obesity-driven large VLDL-triglyceride secretion rate.

Conclusions: In women, abdominal obesity is a major driver of hepatic large VLDL particle secretion, whereas postmenopausal status was characterized by increased small VLDL particle size. These data provide a mechanistic basis for the hyperlipidemia observed in postmenopausal obesity.

Keywords: apolipoproteins; cholesterol; lipids; lipoproteins; menopause; women.

Figure 1

Significant correlations between variables relating to VLDL‐TG metabolism represented as hive plots for premenopausal (A) and postmenopausal (B) women. Each variable is represented by a node and the nodes are joined by blue (significant positive correlations) or red (significant negative correlations) lines. The thickness of the line represents the strength of the correlation. The nodes are placed on 3 duplicated radial axes that represent grouped variables (anthropometric and metabolic variables/VLDL ₁ or VLDL ₂). Individual nodes are coded as indicated and specific correlation coefficients are given in Supplemental Material. Node codes: A, liver fat (%); B, total body fat (kg); C, android fat/total fat; D, gynoid fat/total fat; E, visceral fat (cm²); F, subcut fat (cm²); G, NEFA (μmol/L); H, 3OHB (AUC); I, HOMA‐IR; K, VLDL‐TG SCD isotopic index; M, VLDL‐TG SCD18 index; O, VLDL‐TG 18:2n‐6 (%); Q, VLDL‐TG production per day; S, VLDL‐TG SCD16; U, VLDL‐TG DNL (%); W, VLDL‐TG production/apoB production. 3OHB indicates plasma 3‐hydroxybutyrate; apoB, apolipoprotein B; AUC, area under the curve; DNL, hepatic de novo lipogenesis; HOMA‐IR, homeostatic model assessment of insulin resistance; NEFA, plasma nonesterified fatty acids; SCD, stearoyl‐CoA desaturase; SCD16, 16:1 n‐7/16:0 ratio in VLDL‐TG; SCD18, 18:1 n‐9/18:0 ratio in VLDL‐TG; subcut, subcutaneous; TG, triglyceride; VLDL, very low‐density lipoprotein.

Figure 2

Correlations between VLDL ₁‐TG production (mg/day) and the proportion (%) of DNL fatty acids VLDL ₁‐TG (A), VLDL ₂‐TG direct production (mg/day) and the proportion (%) of DNL fatty acids VLDL ₂‐TG (B), the proportion (%) of DNL fatty acids VLDL ₁‐TG and the AUC for plasma 3‐hydroxybutyrate (μmol/L) (C), the proportion (%) of DNL fatty acids VLDL ₂‐TG and the AUC for plasma 3‐hydroxybutyrate (μmol/L) (D), and the association between plasma 3‐hydroxybutyrate concentrations (μmol/L) and the isotopic desaturation index ([U¹³C16:1n‐7/U¹³C16:0]*1000) in VLDL ₁‐TG (E) and VLDL ₂‐TG (F) in pre‐ (●) and post‐ (○) menopausal women. AUC indicates area under the curve; DNL, hepatic de novo lipogenesis; NS, not significant; TG, triglyceride; VLDL, very low‐density lipoprotein.

Figure 3

Correlations between VLDL ₁‐apoB production (mg/day) and VLDL ₁‐TG production (mg/day) (A), VLDL ₂‐apoB production (mg/day) and VLDL ₂‐TG direct production (mg/day) (B) in pre‐ (●) and post‐ (○) menopausal women. apoB, apolipoprotein B; NS, not significant; TG, triglyceride; VLDL, very low‐density lipoprotein.