Pathophysiology of Non-Alcoholic Steatohepatitis and Basis for Treatment

Pinzani, Massimo

doi:10.1159/000323928

Cited by 28 publications

(34 citation statements)

References 109 publications

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“…Very few breakthroughs have, however, occurred in therapeutic intervention of this disease. 9 Research developing novel, safe, and effective anti-fibrotic strategies is, thus, of the highest priority. 10 Hepatic stellate cells (HSC) are the major effectors during hepatic fibrogenesis.…”

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confidence: 99%

Perilipin 5 restores the formation of lipid droplets in activated hepatic stellate cells and inhibits their activation

Lin

Chen

2016

Laboratory Investigation

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Hepatic stellate cells (HSC) are major effectors during hepatic fibrogenesis. The activation of HSC is coupled to the loss of lipid droplets (LDs), which are specialized organelles composed of neutral lipids surrounded by perilipins. LDs have emerged as a focal point of interest in understanding the metabolic regulation of intrahepatic lipids during lipid-mediated liver fibrogenesis. Perilipin 5 (Plin5) is a newly identified LD protein in the perilipin family, which plays a key role in regulating aspects of intracellular trafficking, signaling, and cytoskeletal organization in hepatocytes. Recent work in Plin5 knockout mice suggests a role in high fat diet-induced hepatic lipotoxicity. The current report is to evaluate the impact of Plin5 on HSC activation and to elucidate the underlying mechanisms. We now show that high fat diet-induced liver fibrosis is accompanied by an approximate 75% reduction in Plin5 in HSC, and that spontaneous activation of primary HSC produces temporally coincident loss of Plin5 expression and LD depletion. As modulating lipid content in HSC is a suggested strategy for inhibition of HSC activation and treatment of hepatic fibrosis, we asked whether exogenous Plin5 expression in primary HSC would reverse the activation phenotype and promote LD formation. Recombinant lentiviral Plin5 expression in primary mouse HSC restored the formation of LDs, increased lipid content by inducing expression of pro-lipogenic genes and suppressing expression of pro-lipolytic genes, and suppressed HSC activation (~two fold reduction in expression of procollagen and α-smooth muscle actin, two unique biomarkers for activated HSC). In addition, the expression of exogenous Plin5 in HSC attenuated cellular oxidative stress by reducing cellular reactive oxygen species, elevating cellular glutathione, and inducing gene expression of glutamate-cysteine ligase. Taken together, our results indicate that expression of Plin5 plays a critical role in the formation of LDs, the elevation of lipid content in HSC, and the inhibition of the activation of HSC.

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confidence: 99%

Perilipin 5 restores the formation of lipid droplets in activated hepatic stellate cells and inhibits their activation

Lin

Chen

2016

Laboratory Investigation

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“…Another potential mechanism by which NAFLD may increase CVD risk is abnormal lipoprotein metabolism. Therefore, enhanced oxidative stress, inflammation with release of inflammatory cytokines and abnormal lipoprotein metabolism could account for the proatherogenic effect of NAFLD [5,13,22,23,24]. …”

Section: Discussionmentioning

confidence: 99%

Nonalcoholic Fatty Liver Disease (NAFLD) And Cardiovascular Risk In Renal Transplant Recipients

Mikolašević¹,

Rački²,

Zaputović

et al. 2014

Kidney Blood Press Res

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Background/Aims: Renal transplant recipients (RTRs) are at high risk for cardiovascular (CVD) mortality. Recently, nonalcoholic fatty liver disease (NAFLD) has been recognized as a new risk factor for adverse CVD events in the general population. We examined whether transient elastography (TE) defined NAFLD was associated with atherosclerosis in RTRs, as measured by ultrasound in the carotid arteries. Methods: Carotid atherosclerosis was assesses in 71 RTRs with a TE proven NAFLD. With the help of TE liver stiffness was used to assess liver fibrosis and Controlled Attenuation Parameter (CAP) was used to detect and quantify liver steatosis. NAFLD was defined by the presence of steatosis with CAP values ≥238 dB.m^-1. Results: RTRs with NAFLD showed more carotid atherosclerosis than RTRs without NAFLD. RTRs-NAFLD patients had the mean intima-media measurements (ITM) of 1.1±0.1 mm and that was statistically significant higher than the mean ITM founded in RTRs without NAFLD (1.1±0.1 vs. 0.9±0.1 mm; p<0.0001). Furthermore, RTRs-NAFLD patients had statistically significant higher prevalence of plaques in comparison with RTRs without NAFLD (p=0.021). Conclusion: We showed for the first time that carotid atherosclerosis is advanced in RTRs with NAFLD. Detection of NAFLD by TE should alert to the existence of an increased cardiovascular risk in RTRs.

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“…Adiponectin, leptin, TNF-α, and IL-6 play critical roles in the process of inflammation and liver injury 52 ( Figure 1). Several studies have demonstrated that autophagy exhibits cellular protective effects, leading cells to survival from death stimuli.…”

Section: Autophagy and Steatohepatitismentioning

confidence: 99%

Autophagy, a new target for non-alcoholic fatty liver disease therapy

Mao¹

2015

WCJD

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Nonalcoholic fatty liver disease (NAFLD) has gained importance in recent decades due to drastic changes in diet, especially in Western countries. NAFLD occurs as a spectrum from simple hepatic steatosis, steatohepatitis to cirrhosis, and even hepatocellular carcinoma. Although the molecular mechanisms underlying the development of NAFLD have been intensively investigated, many issues remain to be resolved. Autophagy is a cell survival mechanism for disposing of excess or defective organelles, and has become a hot spot for research. Recent studies have revealed that autophagy is linked to the development of NAFLD and regulation of autophagy has therapeutic potential. Autophagy reduces intracellular lipid droplets by enclosing them and fusing with lysosomes for degradation. Furthermore, autophagy is involved in attenuating inflammation and liver injury. However, autophagy is regarded as a double-edged sword, as it may also affect adipogenesis and adipocyte differentiation. Moreover, it is unclear as to whether autophagy protects the body from injury or causes diseases and even death, and the association between autophagy and NAFLD remains controversial. This review is intended to discuss, comment, and outline the progress made in this field and establish the possible molecular mechanism involved.

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Pathophysiology of Non-Alcoholic Steatohepatitis and Basis for Treatment

Cited by 28 publications

References 109 publications

Perilipin 5 restores the formation of lipid droplets in activated hepatic stellate cells and inhibits their activation

Perilipin 5 restores the formation of lipid droplets in activated hepatic stellate cells and inhibits their activation

Nonalcoholic Fatty Liver Disease (NAFLD) And Cardiovascular Risk In Renal Transplant Recipients

Autophagy, a new target for non-alcoholic fatty liver disease therapy

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