# A Review on Bioactive Compounds and Pharmacological Activities of _Citrus unshiu_
## 4 Pharmacological Activities of Satsuma Mandarin
### Hepatoprotective and Lipid-Lowering Activities  
Few studies have examined the hepatoprotective and lipid-lowering activities of _C. unshiu_ bioactives in vitro and in vivo. An experiment was designed to evaluate the protective effect of _C. unshiu_ peel extracts against non-alcoholic fatty liver disease in mouse hepatocyte cells (AML12) and high-fat-diet-fed rats. Cells were treated with _C. unshiu_ extracted through hot-air-drying (50 \({}^{\circ}\)C for 72 h) at different concentrations (25, 50, and 100 \(\upmu\)g/mL). High-performance liquid chromatography was used to analyze _C. unshiu_ extracts. Rats were randomized into different groups to receive double-distilled water, a 60% high-fat diet, a 60% high-fat diet with double-distilled water and _C. unshiu_ extracts (50/100 mg/kg), and a 60% high-fat diet with metformin (100 mg/kg). Hesperidin, the major extract of _C. unshiu_, activated AMPK phosphorylation and regulated palmitate-induced hepatocyte steatosis \begin{table}
\begin{tabular}{c c c c c c} \hline \hline \multirow{2}{*}{**Model Type**} & \multirow{2}{*}{**Bioactive Compounds**} & \multirow{2}{*}{**Extraction Techniques and Application in Treatment**} & \multicolumn{2}{c}{**Therapeutic Activities/ Mechanisms**} & \multirow{2}{*}{**Target Genes/Signaling Pathways**} & \multirow{2}{*}{**Ref.**} \\ \hline  & & 3T3-L1 cells were treated & & & \\  & & with Jeju roasted peel & & & \\  & & extract at concentrations & & & \\  & & range from 50 to & & & \\
3T3-L1 adipocyte & & 200 mg/mL. & Reduced lipid & \(\upgamma\)-GTP \(\uparrow\) & \\ cells, C57 BL/6 & \multirow{2}{*}{NA} & \multirow{2}{*}{Mice were randomized to receive a normal diet, high-fat diet (containing 60\% kcal from fat), and high-fat diet supplemented with Jeju roasted peel extract (25/50 mg/kg/bw).} & Reduced lipid & \(\upgamma\)-GTP \(\uparrow\) & \\  & & & & & Lipogenic genes: \\  & & & & & \\  & & & & & \\ \hline  & & Rats were first fed with a & & & \\  & & standard diet (Oriental & & & \\  & & yeast) for 10 weeks and & & & \\  & & injected with & & & \\ Wistar rats & NA & Streptozotocin (75 mg/kg) & & & \\  & & dissolved in a citrate buffer. & & & \\  & & Rats were then assigned to & & dysfunction & \\  & & three groups: 0\%, 1\%, or 3\% & & & \\  & & (wt/wt) C. _unshiu_-treated & & & \\  & & diabetic groups. & & & \\ \hline  & & & Reduced & & \\  & & & & glucose/non- & \\  & & & 3\% (_wt/wt) C. unshiu_ for & fasting blood & & \\  & diabetes & & 10 weeks. & & \\ \hline  & & Mice were supplemented & & & \\  & & & with rosiglitazone & & \\  & & & (0.001 g/100 g diet) or & & \\  & & & _C. unshiu_ peel ethanol & & \\  & & extract (2 g/100 g diet) for & & & \\ C57 BL/KsJ-\(db\)/\(db\) & & & & & \\ type 2 diabetic & \multirow{2}{*}{Hesperidin, narirutin} & 6 weeks. The extraction of & & & \\  & & 50 g dried & _C. unshiu_ peel & & \\ mice & & & & \\  & & & was performed with 1 kg of & & \\  & & & 60\% ethanol by incubation & & \\  & & & at 70 \({}^{\circ}\)C for 3 h. The & & \\  & & & extracts were then cooled, & \\  & & & filtered, and freeze-dried at & & \\  & & & \(-\)40 \({}^{\circ}\)C. & & \\ \hline \hline \end{tabular} ((\(\downarrow\)) Decrease; (\(\uparrow\)) increase; NA = not available.  
\end{table} 
Table 4: _Cont._in AML12 cells by inhibiting the mammalian target of rapamycin complex 1 (mTORC1)- endoplasmic reticulum (ER) stress pathway. Administration of _C. unshiiu_ and hesperidin also reduced hepatic fat accumulation in high-fat-diet-fed rats by decreasing triglycerides levels, total cholesterol, lipid peroxidation, alanine aminotransferase (ALT), and aspartate aminotransferase (ASAT) through activating the AMPK pathway and suppressing the mTOR-ER stress response associated with ROS accumulation [76]. Another experiment evaluated the hepatoprotective effects of Diospyros kaki and _C. unshiiu_ mixture on nonalcoholic fatty liver disease in high-fat-diet-fed rats. Boiling water was used to extract 500 g of dried _C. unshiiu_ peel. Rats were orally administered a 45% high-fat diet for 23 weeks (control group) and _C.