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"Nama : Irena UjiantiProgram Studi : Program Magister Ilmu BiomedikJudul Tesis :Dampak Restriksi Vitamin B12 Terhadap Kadar Homosistein, Resistensi Insulin Dan Gambaran NAFLDPembimbing : dr. Imelda Rosalyn Sianipar, M.Biomed, Ph.D dan Dr. dr. Dewi Irawati Soeria Santoso, MS Latar Belakang: Perlemakan hati merupakan penyakit hati kronik terbesar di dunia. Kondisi yang mendasari terjadinya perlemakan hati dimulai dari kondisi resistensi insulin. Salah satu patogenesis terjadinya resistensi insulin adalah gangguan pada pensinyalan insulin oleh zat toksik tertentu yang akan berinteraksi dengan protein yang menyusun jalur pensinyalan insulin. Peningkatan homosistein dikaitkan dengan resistensi insulin. Homosistein akan meningkat sejalan dengan terganggunya jalur metilasi dari siklus metionin. Pemberian diet restriksi vitamin B12 akan memicu terjadinya resistensi insulin lewat jalur stres oksidatif yang ditimbulkan oleh homosistein.Bahan dan Metode: Penelitian ini menggunakan metode eksperimental terhadap 24 tikus Sprague Dawley jantan Rattus norvegicus, 300-350 gram, usia 35-40 minggu , terbagi ke dalam 4 kelompok yaitu kontrol K , Kelompok perlakuan 4 minggu P-1 , Kelompok Perlakuan 8 minggu P-2 dan kelompok perlakuan 12 minggu P-3 . Pada Kelompok kontrol, diberikan diet standar AIN-93M sedangkan kelompok perlakuan diberikan pakan modifikasi restriksi vitamin B12 AIN-93 sesuai usia perlakuan.Hasil: Kelompok perlakuan 8 minggu paling baik dalam menggambarkan kondisi perlemakan hati dibandingkan kelompok kontrol dan perlakuan 4 minggu, sedangkan kelompok perlakuan 12 minggu telah mempresentasikan kondisi NASH Non Alcoholic Steatohepatitis . Hasil ini sejalan dengan kondisi peningkatan homosistein plasma pada kelompok kontrol dan masing-masing usia perlakuan.Kesimpulan: Peningkatan homosistein akibat diet restriksi vitamin B12 mengakibatkan kondisi steatosis dan steatohepatitits pada hati, sebagai akibat dari kondisi resistensi insulin dan kerusakan sebagian dari sel beta pankreas. Kata kunci: Homosistein, Restriksi vitamin B12, NAFLD, Resistensi Insulin

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ABSTRACT Name Irena UjiantiStudy Program Master Program of Biomedical SciencesThesis Title Impact of Vitamin B12 Restriction on Homocysteine Levels, Insulin Resistance and NAFLDCounselor dr. Imelda Rosalyn Sianipar, M.Biomed, Ph.D. dr. Dewi Irawati Soeria Santoso, MS Background The fatty liver is the biggest chronic liver disease in the world. The underlying condition of fatty liver starts from the condition of insulin resistance. One of the pathomechanisms of insulin resistance is the disturbance in insulin signaling by certain toxic substances that will interact with one of the proteins that make up the insulin signaling pathway. Increased homosisteine is associated with insulin resistance. Homosisteine will increase in line with the disruption of the methionin metionin pathway. Dietary vitamin B12 deficiency will trigger insulin resistance through the path of oxidative stress generated by homocysteine.Materials and Methods This study used an experimental method of 24 male Sprague Dawley rats Rattus norvegicus, 300 400 gram, age 7 8 months , divided into 4 groups kontrol K , 4 weeks treatment group P 1 , 8 weeks treatment group P 2 and 12 week treatment group P 3 . In the kontrol group, a standard AIN 93 diet was administered while the feeding group was administered vitamin A deficiency deficiency AIN 93M according to treatment age.Results The best 8 weeks treatment group described the conditions of fatty liver compared to the 4 week kontrol and treatment group, while the 12 week treatment group presented the NASH condition. These results are consistent with the elevated plasma homocysteine conditions in the kontrol group and each treatment age.Conclusion Increased homocysteine due to dietary vitamin B12 deficiency is able to induce the condition of steatosis and steatohepatitits in the liver, as a result of the condition of insulin resistance and beta cell pancrease damage as the underlying patomechanism. Keywords Homocysteine, vitamin B12 Deficiency, NAFLD, Insulin Resistance "

"Belum banyak studi mempelajari keterkaitan antara defisiensi vitamin B12 dan toksisitas homosistein. Hiperhomosisteinemia dikaitkan dengan penyakit selular terkait NAFLD. Toksisitas homosistein dapat berupa steatosis atau inflamasi sel hati. H. sabdariffa. dan konstituen aktifnya memiliki efek pencegahan terhadap cedera seluler. Ekstrak H. sabdariffa. diuji pada tikus Sprague-Dawley (SD) dalam penelitian ini.Penelitian ini untuk melihat efek H.sabdariffa terhadap peningkatan homosistein pada hati tikus SD yang diberikan diet resriksi vitamin B12.Penelitian ini merupakan penelitian in vivo yang dilakukan di Fakultas Kedokteran Universitas Indonesia. Sebanyak 30 ekor tikus SD dibagi menjadi enam kelompok sesuai waktu perlakuan di 8 dan 16 minggu sebagai berikut: Kelompok kontrol diberikan diet standar AIN-93M, kelompok restriksi vitamin B12 diberi diet AIN-93M dengan modifikasi pengurangan komponen vitamin B12 dan kelompok restriksi vitamin B12 diberi AIN-93M dengan modifikasi pengurangan komponen vitamin B12 ditambah ekstrak etanol H.sabdariffa (HSE). Setelah 8 dan 16 minggu, kadar vitamin B12 dan homosistein diukur. Peningkatan aktivitas toksisitas homosistein dilihat dari ekspresi protein GRP78, SREBP1c dan NF-kB. Aktivitas hepatoprotektif HSE dinilai menggunakan AST, ALT, GGT, dan NAFLD Activity Score (NAS).Kadar vitamin B12 pada 8 minggu (233 ± 10.8 vs 176 ± 5.4 pg/L; p < 0.001) dan 16 minggu (226 ± 13 vs 190 6 pg/L; p < 0,001), lebih tinggi secara bermakna pada kelompok restriksi vitamin B12 dengan diet HSE dibandingkan kelompok diet restriksi vitamin B12 tanpa HSE. Kadar plasma homosistein plasma lebih rendah secara bermakna pada kelompok restriksi vitamin B12 dengan HSE dibandingkan kelompok restriksi vitamin B12 tanpa HSE di usia perlakuan 8 minggu (2,25 ± 0,07 vs 2,63 ± 0,1 mol/L; p < 0,001) dan 16 minggu (2,18 ± 0,07 vs 2,64 ± 0,09 mol/L; p < 0,001). Aktivitas GGT plasma di usia 16 minggu perlakuan menurun secara bermakna pada kelompok restriksi vitamin B12 dengan HSE dibandingkan kelompok restriksi vitamin B12 tanpa HSE (14,5 ± 1,1 vs 22,9 ± 2,4 IU; p < 0,05). Ekspresi protein GRP78, SREBP1c, dan NfKB diukur menggunakan protein GADPH sebagai kontrol internal. Pada minggu ke-8 dan 16, ekspresi protein NF-kB lebih rendah pada kelompok restriksi vitamin B12 dengan HSE dibandingkan dengan grup restriksi vitamin B12 tanpa HSE (0,78 ± 0,08 vs 1,08 ± 0,06; p < 0,05). Ekspresi protein SREBP1c lebih rendah pada kelompok restriksi vitamin B12 dengan HSE dibandingkan dengan grup restriksi vitamin B12 tanpa HSE pada usia perlakuan 16 minggu (0,55 ± 0,03 vs 1,00 ± 0,02; p < 0,05). Kelompok restriksi vitamin B12 dengan HSE memiliki gambaran histopatologis steatosis, inflamasi, dan fibrosis lebih baik dibandingkan kelompok yang restriksi vitamin B12 tanpa HSE setelah 16 minggu perlakuan.Disimpulkan peningkatan homosistein akibat diet restriksi vitamin B12 pada tikus SD menyebabkan steatosis hati, inflamasi, dan fibrosis. Ekstrak etanol H.Sabdariffa memiliki efek pencegahan terhadap kondisi steatosis, inflamasi dan fibrosis akibat peningkatan homosistein pada tikus SD yang diberi diet restriksi vitamin B12.

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There haven't been many studies on the link between vitamin B12 deficiency and homocysteine toxicity. Homocysteine is linked to NAFLD-related cellular disease, and toxicity can manifest as steatosis or inflammation of the liver cells. H. sabdariffa. and its active constituents have a preventive effect against cellular injury. H. sabdariffa extract was tested on Sprague-Dawley (SD) rats with NAFLD in this study. This study aimed to examine the effect of H. sabdariffa on increasing homocysteine ​​in the liver of SD rats fed a vitamin B12 restriction diet.

This research is an in vivo study conducted at the Faculty of Medicine, University of Indonesia. 30 SD rats were divided into six groups based on treatment time at 8 and 16 weeks, with the following treatments: the control group received the standard AIN-93M diet, the vitamin B12 restriction group received the AIN-93M diet with a modified reduction of the vitamin B12 component, and the vitamin B12 restriction + HSE group received the AIN-93M diet with a modified reduction of the vitamin B12 component and an ethanol extract of H. sabdariffa (HSE). After 8 and 16 weeks, vitamin B12 and homocysteine ​​levels were measured. The increase in homocysteine ​​toxicity activity was seen from the expression of GRP78, SREBP1c, and NF-kB proteins. The hepatoprotective activity of HSE was assessed using the AST, ALT, GGT, and NAFLD Activity Score (NAS).

Vitamin B12 levels at 8 weeks (233 ± 10.8 vs 176 ± 5.4 pg/L; p < 0.001) and 16 weeks (226 ± 13 vs 190 6 pg/l; p < 0.001), significantly higher in the HSE group with a vitamin restriction diet. B12. Plasma homocysteine ​​levels were significantly lower in the vitamin B12 restriction group with HSE than in the vitamin B12 restriction group without extract at 8 weeks of age (2.25 ± 0.07 vs. 2.63 ± 0.1 mol/L; p < 0.001 ) and 16 weeks (2.18 ± 0.07 vs. 2.64 ± 0.09 mol/L; p < 0.001). Plasma GGT activity at 16 weeks of treatment decreased significantly in the vitamin B12-restricted group with HSE compared to the vitamin B12-restricted group without HSE (14.5 ± 1.1 vs. 22.9 ± 2.4 IU; p < 0.05). GRP78, SREBP1c, and NfKB protein expressions were measured using GADPH protein as an internal control. At weeks 8 and 16, NF-kB protein expression was lower in the vitamin B12 restriction group with HSE compared to the vitamin B12 restriction group without HSE (0.78 ± 0.08 vs. 1.08 ± 0.06; p < 0 ,05). SREBP1c protein expression was lower in the vitamin B12 restriction group with HSE compared to the vitamin B12 restriction group without HSE at 16 weeks of treatment (0.55 ± 0.03 vs. 1.00 ± 0.02; p < 0.05). The vitamin B12 restriction group with HSE had better histopathological features of steatosis, inflammation, and fibrosis than the vitamin B12 restriction group without HSE after 16 weeks of treatment.

It was concluded that the increase in homocysteine ​​due to dietary restriction of vitamin B12 in SD rats caused liver steatosis, inflammation, and fibrosis. The ethanolic extract of H. Sabdariffa had a preventive effect on steatosis, inflammation, and fibrosis due to increased homocysteine ​​in SD rats fed a vitamin B12 restriction diet."