**4. Placental transfer of maternal lipid and lipoproteins and their metabolites to the fetus**

The human placenta contains VLDL, LDL, HDL, and scavenger receptors as well as LDL receptor-related proteins. The placenta also has LPL, phospholipase-A2 (PLA-2) and intracellular lipase activities as well as plasma membrane fatty acid-binding protein (FABP/GOT2), fatty acid translocase (CD36), fatty acid transfer protein (FATP) and different cytoplasmic FABPs [29, 42,50, 51]. Thus, lipid and lipoproteins in maternal plasma can be taken up and handled by the placenta, allowing LCPUFAs associated with plasma lipoproteins to be transferred to the fetus. The human placenta is capable of transporting free fatty acids(FFAs) by diffusion and selectively increases the transport of essential fatty acids (EFAs) and their long-chain polyunsaturated fatty acids (LCPUFA) derivatives by fatty acid carrier proteins.

Although lipoprotein TGs does not directly cross the placental barrier, the placenta has mechanisms to release fatty acids(FAs) circulating in maternal plasma lipoproteins into the fetus. In addition, high levels of TGs in maternal circulation may create a steep concentration gradient across the placenta, which accelerates their transport and deposition in fetal tissues. In term human trophoblasts, insulin and fatty acids have been shown to enhance the expression of adipophylin, which is associated with cellular lipid droplets and implicated in cellular fatty acid uptake and storage of neutral lipids

#### **4.1. Fatty acids transfer**

52 Lipoproteins – Role in Health and Diseases

**First trimester Second** 

**HDL-C** 67±12 83±19 81±17 69±10 **LDL-C** 90±17 130±46 136±33 99±23 **TGs** 79±27 151±80 245±73 77±34 **TC** 173±18 243±53 267±30 183±23 **ApoA-1** 170±27 204±22 196±28 163±24 **ApoA-2** 49±7 52±6 49±5 47±6 **ApoB** 70±21 91±25 113±29 61±22 **ApoC-11** 265±13 299±18 314±21 237±11 **ApoC-111** 141±3 188±5 217±6 121±19 **ApoE** 41±12 42±9 49±19 42±20 **Lp(a)** 60(0-1440) 63(2-1210) 54(0-1230 86(11-473) **VLDL-1** 19(12-55) 47(26-110) 109(38-170) 23(5-85) **VLDL-2** 17(7-45) 36(20-77) 103946-168) 23(13-44) **IDL** 26(13-54) 58(24-100) 124(79-157) 35(18-62) **Total LDL** 200(135-323) 292(206-410) 353(244-534) 207(150-363) **LDL-1** 33(16-52) 49(37-70) 67(27-96) 50(22-130) **LDL-11** 143(95-231) 160(103-287) 201(59-316) 135(72-258 **LDL-111** 28(15-56) 32(24-165) 123(43-192) 31(5-68) **Table 2.** The increasing lipid and lipoproteins during course of gestation(courtesy: Ahmet Basaran,

**4. Placental transfer of maternal lipid and lipoproteins and their** 

The human placenta contains VLDL, LDL, HDL, and scavenger receptors as well as LDL receptor-related proteins. The placenta also has LPL, phospholipase-A2 (PLA-2) and intracellular lipase activities as well as plasma membrane fatty acid-binding protein (FABP/GOT2), fatty acid translocase (CD36), fatty acid transfer protein (FATP) and different cytoplasmic FABPs [29, 42,50, 51]. Thus, lipid and lipoproteins in maternal plasma can be taken up and handled by the placenta, allowing LCPUFAs associated with plasma lipoproteins to be transferred to the fetus. The human placenta is capable of transporting free fatty acids(FFAs) by diffusion and selectively increases the transport of essential fatty acids (EFAs) and their long-chain polyunsaturated fatty acids (LCPUFA) derivatives by

Although lipoprotein TGs does not directly cross the placental barrier, the placenta has mechanisms to release fatty acids(FAs) circulating in maternal plasma lipoproteins into the fetus. In addition, high levels of TGs in maternal circulation may create a steep concentration gradient across the placenta, which accelerates their transport and deposition in fetal tissues. In term human trophoblasts, insulin and fatty acids have been shown to

**trimester Third trimester Nonpregnant** 

**controls** 

**Lipid and lipoproteins (mg/dl)** 

MD)

**metabolites to the fetus** 

fatty acid carrier proteins.

The supply of LCPUFA is important for fetal growth and tissue development especially for the development of the nervous system and the considerable requirements of these LCPUFAs in the fetus must be provided by their placental transfer [52]. The plasma membrane fatty acid-binding proteins present in human placental membrane [51,52] are responsible for the preferential uptake of LCPUFAs. A selective cellular membrane of certain FAs may also contributes to the placental transfer process, as would the conversion of a certain proportion of arachidonic acid(AA) to prostaglandins(PGs)[52], the incorporation of some FAs into phospholipids[50-52], the oxidation of placental fatty acids[53] and the synthesis of FAs[52,53]. Even though essential fatty acids(EFA) as well as LCPUFAs are transferred across the placenta, the fetus needs to receive substantial amounts of preformed AA and docosahexaenoic acid(DHA) which can be synthesized to a limited extent from the EFA. The two dietary EFAs are linoeic acid(18:2ω-6) and α-linolenic acid(18:3ω-3), which are precursors of the ω-6 and ω-3 LCPUFA, respectively. The synthesis of AA and DHA do not take place in the fetus or the placenta in substantial amounts, owing to the low activities of the desaturating enzymes. Both AA and DHA are abundant in the brain and the retina and their appropriate supply during pregnancy and the neonatal period is critical for proper function [1,54]. Maternal plasma NEFA, though in smaller proportion than lipoprotein TGs, is an important source of polyunsaturated fatty acids(PUFAs) for the fetus [51,52]. Maternal plasma NEFAs correlates with those in the fetus and maternal adipocytokines have been associated with fetal growth[1]. The combination of these processes determines the actual rate of placental FAs transfer and its selectivity, consequent to the proportional enrichment of certain LCPUFAs, such as AA and DHA in fetal as compared with maternal compartments [52, 54].

#### **4.2. Cholesterols**

Cholesterol plays a key role in embryonic and fetal development hence the demands for cholesterol in the embryo and fetus is relatively high. Cholesterol is an essential component of cell membrane influencing the fluidity and passive permeability by interacting with phospholipids and sphingolipids [55]. It's the precursor of bile acids and steroid hormones. It is also required for cell proliferation and development of the growing body, cell differentiation, and cell-to-cell communications, and is the precursor of oxysterol, which regulates key metabolic processes. Available cholesterol in fetus is contributed by: (1) transfer from the mother especially during the first half of the gestation and too little cholesterol due to lack of maternal cholesterol or reduced expressions of placental lipoprotein receptors is correlated with small fetuses and a trends for microcephally; and (2) Fetal synthesis especially during the last half of gestation. Too little cholesterol due to lack of synthesis leads to a spectrum of congenital defects as seen in infants with Smith-LomliOpitz Syndrome(SLOS) who are unable to synthesize cholesterol at normal rate due to null/null mutations in 3β-hydroxysteriod Δ7-reductase, the enzyme that converts 7 dehydrocholesterol to cholesterol. The placental endothelial cells are capable of transporting substantial amounts of cholesterol to the fetal circulation and this mechanism is further enhanced by liver-X receptors and induced up regulation of ATP-binding cassette transporter, ABCA1 and ABCG1[56].

#### **4.3. Glycerol**

Maternal Plasma glycerol levels are consistently elevated during late pregnancy, but crosses the placenta less than glucose or L-alanine [1,25, 57] though they all have similar molecular weights. Transfer of maternal glycerol via the placenta is by simple diffusion (2). However, its effective and rapid utilization through other pathways, such as gluconeogenesis and glyceride glycerol synthesis in the mother[10,25] results in its low plasma concentration and this very active kinetics impede the formation of the adequate gradient to create the appropriate driving forces for its placental transfer.

#### **4.4. Ketone bodies**

In the 3rd trimester of pregnancy, under fed conditions, plasma ketone body concentrations remain low although are greatly increase compared to nonpregnant condition under fasting [58] consequent to enhanced adipose tissue lipolysis. The lipolysis accelerates delivery of NEFA to the liver and enhanced ketogenesis. Ketone bodies can easily cross the placenta and be used as fuels and lipogenic substrates by the fetus. The transfer of ketone bodies across the placenta occurs either by simple diffusion or by a low-specificity carrier-mediated process [25]. The activities of ketone body metabolizing enzyme are present in fetal tissues (brain, liver and kidneys)[1,25] and can be increased by conditions of maternal ketonaemia such as occurs in starvation, during late pregnancy[39] or high-fat feeding[25]. Ketone bodies are used by the fetus as oxidative fuels as well as substrates for brain lipid synthesis [25]. However, in maternal hyperketonaemia as occurs in poorly controlled diabetes patients associated with transfer of excessive arrival of ketone bodies to the fetus seems to be responsible for the major damages [10], increasing stillbirth rate, incidence of malformations, and impaired neurophysiologic development [10]. Subsequently, it could be recommended that pregnant mothers, if possible, should avoid starvation and high fat diet especially in the 3rd trimester.
