Effect of Weight Loss Medications on Hepatic Steatosis and Steatohepatitis: A Systematic Review

Pan, Chelsea S; Stanley, Takara L.

doi:10.3389/fendo.2020.00070

Cited by 38 publications

(42 citation statements)

References 80 publications

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“…Currently, the most-popular weight-loss inducing medications associated with at least 5% body weight decrease in one year as compared to placebo are orlistat, the fixed combination of phentermine and topiramate or naltrexone and bupropion, and the glucagon-like peptide-1 (GLP-1) receptor agonist (GLP-1ra), liraglutide [97]. Of these drugs, orlistat treatment failed to improve liver histology when compared to placebo [98], while no reports are available for topiramate, naltrexone, bupropion and phentermine regarding hepatic endpoints in humans with NAFLD [99]. Only liraglutide treatment associated with the resolution of NASH without worsening of fibrosis in overweight/obese persons (mean values; liraglutide 34.2 vs. placebo 37.7 kg/m 2 ) [100].…”

Section: Antiobesity Drugsmentioning

confidence: 99%

Metabolic liver disease in diabetes – From mechanisms to clinical trials

et al. 2020

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Non-alcoholic fatty liver disease (NAFLD) comprises fatty liver (steatosis), non-alcoholic steatohepatitis (NASH) and fibrosis/cirrhosis and may lead to end-stage liver failure or hepatocellular carcinoma. NAFLD is tightly associated with the most frequent metabolic disorders, such as obesity, metabolic syndrome, and type 2 diabetes mellitus (T2DM). Both multisystem diseases share several common mechanisms. Alterations of tissue communications include excessive lipid and later cytokine release by dysfunctional adipose tissue, intestinal dysbiosis and ectopic fat deposition in skeletal muscle. On the hepatocellular level, this leads to insulin resistance due to abnormal lipid handling and mitochondrial function. Over time, cellular oxidative stress and activation of inflammatory pathways, again supported by multiorgan crosstalk, determine NAFLD progression. Recent studies show that particularly the severe insulin resistant diabetes (SIRD) subgroup (cluster) associates with NAFLD and its accelerated progression and increases the risk of diabetes-related cardiovascular and kidney diseases, underpinning the critical role of insulin resistance. Consequently, lifestyle modification and certain drug classes used to treat T2DM have demonstrated effectiveness for treating NAFLD, but also some novel therapeutic concepts may be beneficial for both NAFLD and T2DM. This review addresses the bidirectional relationship between mechanisms underlying T2DM and NAFLD, the relevance of novel biomarkers for improving the diagnostic modalities and the identification of subgroups at specific risk of disease progression. Also, the role of metabolism-related drugs in NAFLD is discussed in light of the recent clinical trials. Finally, this review highlights some challenges to be addressed by future studies on NAFLD in the context of T2DM.

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Section: Antiobesity Drugsmentioning

confidence: 99%

Metabolic liver disease in diabetes – From mechanisms to clinical trials

et al. 2020

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“…No studies have evaluated whether metformin improves longterm patient-oriented outcomes, such as progression from NAFLD to nonalcoholic steatohepatitis, cirrhosis, hepatocellular carcinoma, or death from liver failure. Rather, a considerable body of evidence on the hepatic effects of metformin have yielded mixed results, indicating there is potentially modest benefit that has yet to be confirmed due to the small sample sizes and short terms of the studies and inconsistently reported outcomes (37)(38)(39)(40)(41). NAFLD is intricately linked to insulin resistance and its associated metabolic features (e.g., higher body weight, BMI, and waist circumference), so by improving metabolic features of NAFLD, metformin could also improve management of this liver disease.…”

Section: Discussionmentioning

confidence: 99%

A High-Fat Diet Attenuates AMPK α1 in Adipocytes to Induce Exosome Shedding and Nonalcoholic Fatty Liver Development In Vivo

Cao

Tian²,

et al. 2020

Diabetes

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Exosomes are important for intercellular communication, but the role of exosomes in the communication between adipose tissue (AT) and the liver remains unknown. The aim of this study is to determine the contribution of AT-derived exosomes in nonalcoholic fatty liver disease (NAFLD). Exosome components, liver fat content, and liver function were monitored in AT in mice fed a high-fat diet (HFD) or treated with metformin or GW4869 and with AMPKα1-floxed (Prkaα1 fl/fl /wild-type [WT]), Prkaα1 −/− , liver tissue-specific Prkaα1 −/− , or AT-specific Prkaα1 −/− modification. In cultured adipocytes and white AT, the absence of AMPKα1 increased exosome release and exosomal proteins by elevating tumor susceptibility gene 101 ( TSG101 )–mediated exosome biogenesis. In adipocytes treated with palmitic acid, TSG101 facilitated scavenger receptor class B (CD36) sorting into exosomes. CD36-containing exosomes were then endocytosed by hepatocytes to induce lipid accumulation and inflammation. Consistently, an HFD induced more severe lipid accumulation and cell death in Prkaα1 −/− and AT-specific Prkaα1 −/− mice than in WT and liver-specific Prkaα1 −/− mice. AMPK activation by metformin reduced adipocyte-mediated exosome release and mitigated fatty liver development in WT and liver-specific Prkaα1 −/− mice. Moreover, administration of the exosome inhibitor GW4869 blocked exosome secretion and alleviated HFD-induced fatty livers in Prkaα1 −/− and adipocyte-specific Prkaα1 −/− mice. We conclude that HFD-mediated AMPKα1 inhibition promotes NAFLD by increasing numbers of AT CD36-containing exosomes.

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“…Metformin has a modest benefit on weight loss and, in studies in NAFLD, has generally not demonstrated significant improvements over comparator therapy in serum markers of liver injury, liver fat content, or in histological inflammation and fibrosis 119 . In a study of 85 patients with T2DM and NAFLD, 24 weeks of either metformin or liraglutide significantly improved weight, BMI, and waist circumference versus gliclazide (all P <0.01) 120 ; however, there was a significant reduction in intrahepatic fat content with liraglutide versus gliclazide ( P = 0.001), but not with metformin 121 .…”

Section: Resultsmentioning

confidence: 99%

Nonalcoholic fatty liver disease as a metabolic disease in humans: A literature review

Cariou

Byrne

Loomba

et al. 2021

Diabetes Obesity Metabolism

126

104

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Aims: To conduct a systematic literature review to identify recent epidemiological, biomarker, genetic and clinical evidence that expands our understanding of nonalcoholic fatty liver disease (NAFLD) as a metabolic disorder. Materials and Methods:We performed a literature search using PubMed to identify trials, observational studies and meta-analyses published in the past 5 years.Results: A total of 95 publications met prespecified inclusion criteria and reported on the interplay between NAFLD/nonalcoholic steatohepatitis (NASH) and metabolic dysfunction, in terms of disease burden and/or epidemiology (n = 10), pathophysiology, risk factors and associated conditions (n = 29), diagnosis and biomarkers (n = 34), and treatment approaches (n = 22). There is a growing body of evidence on the links between NAFLD/NASH pathogenesis and mechanisms of metabolic dysfunction, through liver lipid accumulation, insulin resistance, inflammation, apoptosis, and fibrogenic remodelling within the liver. The frequent co-occurrence of NAFLD with obesity, metabolic syndrome and type 2 diabetes supports this premise. Therapeutic approaches originally envisaged for type 2 diabetes or obesity (such as glucagon-like peptide-1 receptor agonists, sodium-glucose co-transporter-2 inhibitors, insulin sensitizers and bariatric surgery) have shown promising signs of benefit for patients with NAFLD/NASH.Conclusions: Given the complex interplay between NAFLD and metabolic dysfunction, there is an urgent need for multidisciplinary collaboration and established protocols for care of patients with NAFLD that are individualized and ideally support reduction of overall metabolic risk as well as treatment for NASH.

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Effect of Weight Loss Medications on Hepatic Steatosis and Steatohepatitis: A Systematic Review

Cited by 38 publications

References 80 publications

Metabolic liver disease in diabetes – From mechanisms to clinical trials

Metabolic liver disease in diabetes – From mechanisms to clinical trials

A High-Fat Diet Attenuates AMPK α1 in Adipocytes to Induce Exosome Shedding and Nonalcoholic Fatty Liver Development In Vivo

Nonalcoholic fatty liver disease as a metabolic disease in humans: A literature review

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