Disertasi

Efek modulasi 6-gingerol pada model tikus sindrom metabolik: Fokus pada jalur endoplasmic reticulum stress. = Effects of 6-gingerol modulation in rat metabolic syndrome models: Focus on the endoplasmic reticulum stress pathway.

Latar Belakang: Sindrom metabolik (MetS) ialah suatu kluster kelainan metabolik yang berhubungan dengan peningkatan risiko penyakit kardiovaskular, diabetes melitus tipe 2, obesitas, serta non-alcoholic fatty liver disease. MetS melibatkan endoplasmic reticulum stress (ER stress) di dalam patogenesisnya. 6-gingerol diketahui memiliki banyak efek farmakologi yang berpotensi untuk pengobatan MetS. Studi ini bertujuan untuk meneliti efek modulasi 6-gingerol terhadap MetS melalui jalur ER stress dan menentukan doseresponse relationship. Metode: Pembuatan model MetS menggunakan tikus Sprague-Dawley jantan yang diberikan diet tinggi lemak tinggi fruktosa (high-fat high fructose, HFHF) selama 16 minggu dan diinjeksi streptozotocin intraperitoneal dosis rendah (22 mg/kgBB) pada minggu ke-8. Dua puluh lima ekor tikus dibagi menjadi kelompok diet standar, kontrol negatif (HFHF) dan 3 kelompok perlakuan yang masing-masing diberikan 6-gingerol dosis 50, 100 dan 200 mg/kgBB selama 8 minggu. 6-gingerol diberikan setelah 8 minggu induksi. Di akhir studi, tikus dikorbankan, diambil serum, jaringan adiposa, hati, usus dan feses di kolon. Selanjutnya dilakukan pemeriksaan antara lain glukosa darah puasa, HOMA-IR, kadar kolesterol total, HDL, LDL dan trigliserida; AST, ALT, ALP; leptin, adiponectin, rasio adiponectin:leptin (rasio A:L), sitokin proinflamasi (IL-6 dan TNFa); calprotectin, mikrobiota; serta parameter ER stress (GRP78, IRE1, TRAF2, JNK dan NF- kB); juga pemeriksaan histopatologi jaringan adiposa dan hati (termasuk penilaian skor NAS, pewarnaan lemak Oil Red O, dan Tunel Test). Hasil: Hasil studi menunjukkan 6-gingerol dapat mengurangi berat badan, menurunkan glukosa darah puasa dan memperbaiki resistensi insulin, menurunkan kadar kolesterol total, LDL dan trigliserida, menurunkan kadar AST, ALT dan ALP, meningkatkan rasio adiponectin/leptin (rasio A/L), menurunkan IL-6 dan TNF- a, menurunkan kadar calprotectin feses, memperbaiki disbiosis dengan menurunkan rasio Firmicutes/Bacteroidota dan meningkatkan bakteri penghasil butirat, mengurangi hipertrofi jaringan adiposa, serta mengurangi progresivitas inflamasi, akumulasi lipid dan apoptosis pada hepatosit secara bermakna (p < 0,05). Perbaikan terhadap kelainan metabolik tersebut terjadi melalui downregulasi ekspresi protein GRP78, IRE1 (dosis 200mg/kgBB), TRAF2 (dosis 100, 200mg/kgBB), p-JNK (dosis 100, 200mg/kgBB), dan p-NF- kB hati (dosis 200mg/kgBB) secara bermakna (p < 0,05). Kesimpulan: Studi ini berhasil membuktikan efek modulasi 6-gingerol pada sindrom metabolik secara dose-dependent melalui jalur ER stress.
Kata Kunci: 6-gingerol, sindrom metabolik, endoplasmic reticulum stress, GRP78, IRE1.


Background: Metabolic syndrome (MetS) is a cluster of metabolic disorders associated with an increased risk of cardiovascular disease, type 2 diabetes mellitus, obesity, and non-alcoholic fatty liver disease. MetS implicates ER stress in its pathogenesis. 6- gingerol is known to have many potential pharmacological effects for treating MetS. This study aims to investigate the modulating effect of 6-gingerol on MetS via the ER stress pathway and determine the dose-response relationship. Methods: To induce MetS, male Sprague-Dawley rats were fed high-fat high fructose (HFHF) diet for 16 weeks and injected with low-dose intraperitoneal streptozotocin (22 mg/kg BW) at week 8. Twenty-five rats were divided into a standard diet group, negative control (HFHF), and three treatment groups with 6-gingerol doses of 50, 100, and 200 mg/kg BW for eight weeks, respectively (given after eight weeks of induction). At the end of the study, all rats were sacrificed; serum, adipose tissue, liver, intestine, and feces were collected in the colon. Then the following tests were carried out, including fasting blood glucose, HOMA-IR, total cholesterol, HDL, LDL, and triglyceride levels; AST, ALT, ALP; leptin, adiponectin, adiponectin: leptin ratio (A:L ratio), proinflammatory cytokines (IL-6 and TNF-α); calprotectin, microbiota; and ER stress parameters (GRP78, IRE1, TRAF2, JNK, and NF- kB); also a histopathological examination of adipose tissue and liver (including NAS score assessment, Oil Red O fat staining, and Tunel Test). Results: 6-gingerol can reduce body weight, lower fasting blood glucose and improve insulin resistance, reduce total cholesterol, LDL, and triglyceride levels, reduce AST, ALT, and ALP levels, increase the adiponectin/leptin ratio (A/L ratio), reduce IL-6 and TNF-α, reduced fecal calprotectin levels, improved dysbiosis by reducing the Firmicutes/Bacteroidota ratio and increasing butyrate-producing bacteria, reduced adipose tissue hypertrophy, and significantly reduced the progression of inflammation, lipid accumulation and apoptosis in hepatocytes (p < 0,05). Improvement of these metabolic abnormalities occurred through downregulation of GRP78 protein expression, IRE1 (dose of 200 mg/kgBW), TRAF2 (dose of 100, 200 mg/kgBW), p-JNK (dose of 100, 200 mg/kgBW), and liver p-NF- kB (dose 200mg/kgBW) significantly (p < 0.05). Conclusion: This study proved the modulating effect of 6-gingerol on metabolic syndrome in a dose-dependent manner through the ER stress pathway.
Keywords: 6-gingerol, metabolic-syndrome, endoplasmic reticulum stress, GRP78, IRE1.