Fat Metabolism, Insulin and MTHFR

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1 Fat Metabolism, Insulin and MTHFR BCAA, SAMe and ACAT Carolyn Ledowsky

2 Overview of This Presentation 1. Fat Metabolism and MTHFR 2. SAMe and Fat Metabolism 3. Acetyl Co A and Fat Metabolism 4. How to Maintain Healthy Fat Metabolism?

3 A case study Male, 60 years of age Very stressed job Having tried to lose weight his whole life Presenting to the clinic at 108 kg (5 7 ) Did not know he had MTHFR until checked Found compound heterozygous MTHFR Being on blood pressure meds/cholesterol meds

4 A case study (cont.) Initial changes Diet One serve of carbs per day No gluten, no dairy Exercises no change as he was doing a lot Methylation good amounts of methyl's and Vitamin B support

5 A case study - results 1 year later, he has lost 14 Kg He said it was so easy Lost 25cm off his waist Lost 15cm around his neck Lost cm off his arms, thighs, Most importantly, he lost 7 points in visceral fat **** a very happy man and 3 years later his weight is consistent.

7 Where does MTHFR fit? Homocysteine Optimal level umol/l Too low is as bad as too high

8 Homocysteine and fat accumulation MTHFR disturbs fat metabolism Lower methylation Higher Homocysteine Fat accumulating in tissues

13 Folic Acid The study goes on to report. The folic acid fed mice had v Lower MTR activity v Lower MTR activity v Lower MAT1A activity v Betaine dropped significantly v Lower SAM/SAH ratio

15 MTHFR gene mutation MTHFR 677TT genotype are at significantly higher risk of: v Overweight v Obesity

16 Fat Metabolism and MTHFR

17 Consequences of fat accumulation Hyperlipidaemia (high levels of fats in the bloodstream) Cardiovascular disease Non-alcoholic fatty liver disease Insulin resistance and diabetes

18 Methylation Genes related to fat metabolism S-adenosylmethionine (SAMe) decreases triglyceride secretion in very-lowdensity lipoproteins (VLDL); excess hepatic SAMe disrupts VLDL assembly and increases circulating VLDL clearance and causes increased VLDL-lipid supply to tissues resulting in non-alcoholic fatty liver

19 Betaine MTHFR and fat and metabolism fat metabolism Betaine, MTHFR and fat metabolism Liver and muscles are the major organs for methyl group metabolism Dietary methyl donors are methionine, folate, betaine, and choline Methyl-deficient diets cause liver issues, fatty livers, and muscle disorders Higher plasma thcy indicates methyl group deficiency from either genetic (MTHFR) or nutritional reasons Folate supplementation spares betaine as a methyl donor Betaine is a significant determinant of plasma thcy, particularly in folate deficiency; and has a lowering effect on post-methionine load thcy Betaine can attenuate hypomethylation and thcy elevation, and prevent fatty liver induced by a high-fat diet

22 SAMe and Fat Metabolism

24 SAMe metabolism

25 SAMe and NASH Triglyceride accumulation results from an imbalance of TG synthesis, VLDL assembly and secretion, de novo lipogenesis and FA beta oxidation. For NASH to develop, multiple pathways are required to develop inflammation, cellular injury and fibrosis. This may include : oxidative stress (increased ROS is a key driver) Iron accumulation Endotoxins Cytokines Changes in the gut liver axis Mitochondrial dysfunction

28 SAMe, methylation and fat metabolism SAM is the sole methyl donor modifying histones, nucleic acids, and lipids The liver is where the bulk of SAMe is generated and it is the organ where about 50% of all dietary methionine is metabolised. In the hepatocyte, SAMe is produced as the result of an interaction between methionine and adenosine triphosphate via the enzyme methionine adenosyltransferase (MAT), while its degradation is dependent on the glycine- N-methyltransferase (GNMT) enzyme. Low SAM is associated with lipid accumulation, tissue injury, and immune dysfunction in fatty liver disease

29 SAMe production

30 SAMe Reduction of Liver SAMe (due to MAT1A genes) leads to development of NAFLD. Low hepatic SAMe reduces PC (Phosphatidylcholine content) that leads to lipogenesis Low liver SAMe disrupts very low density lipoprotein (VLDL) assembly, leading to the synthesis of small, lipid poor VLDL particles and to a decrease in the secretion of triglycerides. Triglyceride accumulation results from an imbalance of TG synthesis, VLDL assembly and secretion, de novo lipogenesis and FA beta oxidation.

31 Phosphatidylcholine PC is produced in the liver via two pathways: 1. CDP-choline pathway = 70% of PC synthesis 2. PEMT = 30%. This is dependent on SAMe. PE is converted to PC by SAMe. (therefore this is affected by MAT1A deficiency. So we have low PC. 1. The decreased PC-PE ratio increases membrane permeability leading to leakage of cellular components, activating Kupfler cells and cytokine release leading to liver cell injury. 2. The reduced SAMe level sensitizes the liver to lipopolysaccharide induced injury and promotes the expression of pro-inflammatory cytokines.

32 GNMT GNMT reduction causes 1. Increased SAMe levels which in turn activates NK cells in the liver and the PEMT pathway results in more PC synthesis. 1. The liver then stimulates VLDL and HDL to restore a normal PC-PE ration and increases PC catabolism leading to increased TG and PC mobilisation SO HIGH AND LOW SAMe LEVELS CAN LEAD TO NASH DEVELOPMENT WITH THE PC-PE RATIO BEING A KEY PLAYER.

33 Acetyl Co A and Fat Metabolism

35 Acetyl- CoA, fat metabolism and obesity Acetyl-CoA as a key indicator of metabolic state In a 'fed' state, its utilization is promoted for lipid synthesis In a 'fasted' states, it is directed into the mitochondria to promote the synthesis of ATP and ketone bodies Under excess lipid and obesity, acetyl-coa inhibits activity of carnitine acetyltransferase, and reduce PDH activity and glucose disposal Acetyl-CoA is a fatty acid precursor A high fat diet increases body fat accumulation by metabolically modulating tissue acetyl-coa levels through acetyltransferase, thereby increasing fatty acid synthesis and reducing oxidation Acetyl-CoA may play a role in obesity induced cancer through regulating protein acetylation to increase inflammation

37 How to maintain healthy fat metabolism?

38 Fat metabolism Optimising methylation will support fat metabolism Key signs and symptoms: Floating stools Nausea Low Vitamin A, D, E, K Inability to lose weight even though diet is good (always had it) Elevated GGT Elevated cholesterol Elevated LDL Elevated VLDL

39 Fat metabolism Optimising methylation will support fat metabolism Genetics to consider: ACAT acetyl CoA MAT1A MTHFR MTR MTRR BHMT MUT MMAB

40 Supplements to consider Supplements to consider: Acetyl L carnitine essential for Fatty acid metabolism. It transports fatty acids from fats into the mitochondrion for subsequent oxidation. Methyl folate assists in the production of SAMe. Essential for PEMT synthesis. Methylcobalamin assists in the production of SAMe Phosphatidylcholine essential for fat absorption and protection of cellular membranes. TMG/B6 help with the recycling and elimination of homocysteine.

41 SAMe When to use SAMe vs methyl folate Assess SAMe levels. Is MAT1A ++ present? If so conversion is the issue. Remember cofactor for MAT1A is magnesium and ATP. Is GNMT ++ present. Cofactor is SAM PEMT ++. Cofactor is SAM If Methyls are not being utilised then SAMe is a good choice but if not use methyl folate. Does the organic acids show disturbance with pyruvate and mitochondrial enzymes?

42 Cellular membrane health Support Cellular membrane health and Reduce ROS CoQ10 scavenges peroxynitrite breakdown products Selenium required for GSH Acetyl L carnitine/carnitine protective role in the mitochondria Phospholipids regenerate the mitochondrial inner membrane Hydroxocobalamin a nitric oxide scavenger Folate decreases the uncoupling of NOS activity. NOS uncoupling causes increase in production of peroxynitrite. So methyl folate supports BH4 regeneration.

43 Back to our patient So what did I give him? Supplements: B12 methyl 2,000mcg per day Cofactor B Vitamin B1, 2, 3, 5. 6 Acetyl L carnitine 500mg breakfast and lunch Then: Folate mcg per day depending on stress levels Phospholipids 800mg bd Diet higher fat, lower carbs. Multi nutrient formula with zinc, molybdenum, selenium Glutathione.

44 THANK YOU AND QUESTIONS CONTACT US: MTHFR Support Australia Join our practitioner membership to hear more of these webinars. Tel: Copyright MTHFR Support Australia All rights reserved. This document may not be copied or Distributed without the prior written permission of Carolyn Ledowsky

Estrogen. Cysteine Prevents oxidation of estrogen into a dangerous form that causes breast cancer. 29,30,31

Estrogen. Cysteine Prevents oxidation of estrogen into a dangerous form that causes breast cancer. 29,30,31 Cysteine Prevents oxidation of estrogen into a dangerous form that causes breast cancer. 29,30,31 Estrogen lowers risk of zinc de ciency; dependent proteins metabolize estrogen. 26,27,28 Magnesium Cofactor