Review article: new treatments in non‐alcoholic fatty liver disease

Townsend, Sarah; Newsome, Philip N.

doi:10.1111/apt.14210

Cited by 57 publications

(53 citation statements)

References 113 publications

(120 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Evidence from animal models suggests that FXR activation may lead to increases in LDLc concentrations and decreases in HDLc concentrations . Clinical evidence, based on OCA administration, indicates the same effects are observed in humans; additional studies using other FXR agonists are underway …”

Section: Discussionmentioning

confidence: 95%

CONTROL: A randomized phase 2 study of obeticholic acid and atorvastatin on lipoproteins in nonalcoholic steatohepatitis patients

Pockros

Fuchs

Freilich

et al. 2019

Liver International

129

View full text Add to dashboard Cite

Background & Aims Nonalcoholic steatohepatitis (NASH) is a chronic and severe form of nonalcoholic fatty liver disease that can progress to cirrhosis and hepatocellular carcinoma and is a risk factor for cardiovascular disease. Although NASH has no approved treatments, obeticholic acid (OCA), a synthetic bile acid and farnesoid X receptor (FXR) agonist, was shown to improve histological features of NASH and fibrosis. Considering that FXR activation influences plasma lipoprotein concentrations, the Combination OCA aNd sTatins for monitoRing Of Lipids (CONTROL) study evaluated how statins can regulate lipoprotein metabolism with OCA treatment in patients with NASH. Methods This randomized, double‐blind, placebo‐controlled, phase 2 study began with a 5‐week screening/statin washout; 84 patients with NASH were randomly assigned (1:1:1:1) to receive placebo or 5 mg, 10 mg or 25 mg OCA once daily during the 16‐week double‐blind phase. Concurrent once daily atorvastatin (10 mg/days) was initiated at Week 4 with subsequent titration. Enrolled patients had biopsy‐confirmed diagnosis of NASH with no evidence of hepatic decompensation. Plasma was collected to analyse lipoprotein parameters. Results At Week 4, all OCA groups had an increase from baseline in mean low‐density lipoprotein cholesterol (LDLc) and mean LDL particle concentration (LDLpc), mostly owing to large, less atherogenic LDLc particles. Atorvastatin 10 mg decreased LDLc and LDLpc levels below baseline in all OCA groups by Week 8; higher doses did not provide additional clinical benefits. Conclusions The CONTROL study showed that OCA‐induced increases in LDLc in patients with NASH were mitigated with atorvastatin. The combination of OCA and atorvastatin was generally safe and well tolerated (NCT02633956).

show abstract

Section: Discussionmentioning

confidence: 95%

CONTROL: A randomized phase 2 study of obeticholic acid and atorvastatin on lipoproteins in nonalcoholic steatohepatitis patients

Pockros

Fuchs

Freilich

et al. 2019

Liver International

129

View full text Add to dashboard Cite

show abstract

“…A reduction of ≥5%‐10% in body weight is needed to obtain a beneficial effect in the reversion of NASH (and fibrosis). Unfortunately, low patient compliance to this approach (even in highly motivated subjects) is the most difficult obstacle …”

Section: Future Perspectivesmentioning

confidence: 99%

Global epidemiology of non‐alcoholic fatty liver disease/non‐alcoholic steatohepatitis: What we need in the future

Araújo

Rosso

Bedogni

et al. 2018

Liver International

342

265

View full text Add to dashboard Cite

The estimated prevalence of non‐alcoholic fatty liver disease (NAFLD) worldwide is approximately 25%. However, the real prevalence of NAFLD and the associated disorders is unknown mainly because reliable and applicable diagnostic tests are lacking. This is further complicated by the lack of consensus on the terminology of different entities such as NAFLD or nonalcoholic steatohepatitis (NASH). Although assessing fatty infiltration in the liver is simple by ultrasound, the gold standard for the assessment of fibrosis, the only marker of progression towards more severe liver disease is still liver biopsy. Although other non‐invasive tests have been proposed, they must still be validated in large series. Because NAFL/NAFLD/NASH and related metabolic diseases represent an economic burden, finding an inexpensive method to diagnose and stage fatty liver is a priority. A translational approach with the use of cell and/or animal models could help to reach this goal.

show abstract

“…The mechanism underlying NAFLD pathophysiology remains elusive; however, a "two-hit" hypothesis has been suggested as a possible mechanism of pathological change in chronic liver disease [3]. Simple hepatic steatosis caused by lipid accumulation represents the "first hit" in the pathological process [4]. Lipid droplets (LDs) are a form of lipid accumulation, which represents an early pathophysiological feature of altered liver metabolism [5].…”

Section: Introductionmentioning

confidence: 99%

Resveratrol Ameliorates Lipid Droplet Accumulation in Liver Through a SIRT1/ ATF6-Dependent Mechanism

Zhou

et al. 2018

Cell Physiol Biochem

View full text Add to dashboard Cite

Background/Aims: Lipid droplets (LDs) are dynamic organelles that store neutral lipids during times of energy excess, and an increased accumulation of LDs in the liver is closely linked to hepatic steatosis. Our previous studies suggested that resveratrol (RSV) supplement could improve hepatic steatosis, but the underlying mechanism, particularly which related to LD accumulation, has not yet been elucidated. Methods: A high-fat diet (HFD) and palmitic acid were used to induce hepatic steatosis in mouse liver and hepatocytes, respectively. The effects of RSV on LD accumulation were analyzed in vivo and in vitro. The effects of RSV on the expression levels of LD-associated genes (ATF6, Fsp27β/CIDEC, CREBH, and PLIN1) were measured by qRT-PCR and western blot assays, followed by KD or overexpression of SIRT1 and ATF6 with small interfering RNAs or overexpressed plasmids, respectively. The dual luciferase reporter assay, chromatin immunoprecipitation assay, coimmunoprecipitation, and proximity ligation assay were utilized to clarify the mechanism of transcriptional regulation and possible interaction between SIRT1 and ATF6. Results: There was a significant increase in the accumulation of LDs in liver and hepatocytes during the process of HFD-induced steatosis, respectively, which was significantly inhibited by RSV supplementation. RSV notably activated SIRT1 expression and decreased the expression levels of ATF6, Fsp27β/CIDEC, CREBH, and PLIN1, which are associated with LD accumulation. Interestingly, the inhibitory effects of RSV on LD accumulation and the associated expression of genes in hepatocytes were abrogated or strengthened with SIRT1 silencing or overexpression, respectively. On the contrary, the benefits of RSV in hepatocytes were eliminated or aggravated when transfected with the overexpressed ATF6 or ATF6 siRNA, respectively. Furthermore, we found that RSV stimulated SIRT1 expression significantly, which was followed by increased deacetylation and inactivation of ATF6, resulting in a positive feedback loop for SIRT1 transcription associated with ATF6 binding to the SIRT1 promoter region. Conclusion: Taken together, these findings indicate that RSV supplementation improves hepatic steatosis by ameliorating the accumulation of LDs, and this might be partially mediated by a SIRT1/ATF6-dependent mechanism.

show abstract

Review article: new treatments in non‐alcoholic fatty liver disease

Cited by 57 publications

References 113 publications

CONTROL: A randomized phase 2 study of obeticholic acid and atorvastatin on lipoproteins in nonalcoholic steatohepatitis patients

CONTROL: A randomized phase 2 study of obeticholic acid and atorvastatin on lipoproteins in nonalcoholic steatohepatitis patients

Global epidemiology of non‐alcoholic fatty liver disease/non‐alcoholic steatohepatitis: What we need in the future

Resveratrol Ameliorates Lipid Droplet Accumulation in Liver Through a SIRT1/ ATF6-Dependent Mechanism

Contact Info

Product

Resources

About