From:  Molecular targets regulating endoplasmic reticulum-mitochondria crosstalk for NAFLD treatment

 Treatment options for NAFLD

MoleculesTargetFunctionReferences
AAEOSAAE protected mitochondrial function and reduced OS by reducing lipid peroxidation and modulating the expression of antioxidant enzymes (e.g., glutathione reductase and catalase).[79]
ISVOxidative and ER stressISV, a derivative of stevioside extracted from the plant Stevia Rebaudiana Bertoni, prevents FFA- and HFD-induced hepatic injury through modulating protein kinase C-β/Src-homology-2-domain-containing transforming protein 1-mediated oxidative and ER stress. ISV also decreased ER-mitochondrial interaction.[80]
PKMitochondrial UCP-2PK promoted mitochondrial function by inhibiting HFD-induced increase of mitochondrial UCP-2 and HFD-induced decrease of cytochrome c and by up-regulating CPT-1, which alleviates NAFLD.[81]
MelatoninMitochondrial fissionMelatonin supplementation halted mitochondrial fission but recovered mitophagy via blockade of NR4A1-DNA-PKcs-p53 pathway, conferring a protective effect to hepatocytes and mitochondrial function.[83]
n-3 PUFAER stress and mitochondrial dysfunctionAnalysis of hepatic proteomics and plasma lipidomics indicated that 6-month treatment with n-3 PUFA significantly ameliorated markers of lipid metabolism, ER stress, and mitochondrial functions in patients with NASH.[89, 97]
MaR1SERCA2bMaR1, a DHA-derived metabolite, inhibited hepatic lipid synthesis and steatosis via activating AMPK/SERCA2b-mediated suppression of ER stress in HFD-fed mice.[81, 92]
Monounsaturated OAER stress, mitochondrial dysfunction, OSTreatment with monounsaturated OA markedly improved PA-induced cellular apoptosis, OS, ER stress, mitochondrial dysfunction, as well as inflammation in hepatocytes.[93]
Astragaloside IV (AS-IV)ER stressTreatment with AS-IV, a bioactive compound isolated from Astragali Radix, attenuated FFA-induced hepatic ER stress in a dose-dependent manner, evidenced by the reduction of the critical markers, GRP78, CHOP, and phospho-protein kinase R-like endoplasmic reticulum kinase (p-PERK). These results suggest that AS-IV is a promising therapeutic agent for hepatic steatosis and NAFLD.[89, 97]
R-Tf-D-LP4VDAC1R-Tf-D-LP4 treatment eliminated hepatocyte ballooning degeneration, inflammation, and liver fibrosis associated with steatosis, NASH, and hepatocarcinoma, and it restored liver pathology-associated enzyme and glucose levels.[98]
SilymarinER stressSilymarin ameliorated NAFLD via inhibiting ER stress proteins GRP78 and XBP-1.[99]