Hepatic lipid droplets: A balancing act between energy storage and metabolic dysfunction in NAFLD

Mashek, Douglas G.

doi:10.1016/j.molmet.2020.101115

Cited by 141 publications

(141 citation statements)

References 243 publications

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“…Interestingly, we found a significant positive association between TGFB protein expression and lipid droplet area, but a weaker association between TGFB protein and the area of fibrosis. A previous study has demonstrated that lipid droplets are prominent in severe steatohepatitis [ 32 ]. Taking the present results together with those of previous studies, it may be that TGFB is expressed in livers with large lipid droplets, and it subsequently induces hepatic fibrosis.…”

Section: Discussionmentioning

confidence: 99%

Consumption of barley ameliorates the diabetic steatohepatitis and reduces the high transforming growth factor β expression in mice grown in α-minimum essential medium in vitro as embryos

Ishiyama

Kimura

Umihira

et al. 2021

Biochemistry and Biophysics Reports

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Non-alcoholic fatty liver disease (NAFLD), which includes the subtype non-alcoholic steatohepatitis (NASH), is a major complication of type 2 diabetic mellitus (T2DM), even among non-obese patients. However, the exact cause of NAFLD/NASH in non-obese patients with T2DM is unclear. We studied a non-obese mouse model of T2DM created through the malnourishment of embryos by culture in vitro for 48 h in α-minimum essential medium (MEM) at the two-cell stage. We compared the development of steatohepatitis in these MEM mice with control mice that were similarly cultured in standard potassium simplex-optimized medium (KSOM). We also studied the effects of 10 weeks of consumption of barley, which contains large amounts of the soluble fiber β-glucan, on the steatohepatitis of the adult MEM mice. The size of lipid droplets, the area of fibrosis, and the mRNA expression of the transforming growth factor beta ( Tgfb ) gene in the liver were higher in adult MEM mice fed a rice-based diet than in KSOM mice fed the same diet. However, barley consumption reduced the area of fibrosis and TGFB expression in MEM mice. In conclusion, adult mice that are cultured in MEM at the two-cell embryo stage develop steatohepatitis and T2DM, accompanied by higher hepatic TGFB expression, than KSOM controls. Furthermore, the consumption of barley during adulthood ameliorates the steatohepatitis and reduces the TGFB expression.

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Section: Discussionmentioning

confidence: 99%

Consumption of barley ameliorates the diabetic steatohepatitis and reduces the high transforming growth factor β expression in mice grown in α-minimum essential medium in vitro as embryos

Ishiyama

Kimura

Umihira

et al. 2021

Biochemistry and Biophysics Reports

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“…Emerging data are redefining the interaction between ATGL-mediated lipolysis and lipophagy in the hydrolysis of hepatic LD TAG [ 34 ]. While traditionally thought of as distinct pathways, two recent studies challenge this schema and provide evidence that ATGL might function in parallel with lipophagy in hepatocytes [ 24 , 25 ].…”

Section: Discussionmentioning

confidence: 99%

Integrated Action of Autophagy and Adipose Tissue Triglyceride Lipase Ameliorates Diet-Induced Hepatic Steatosis in Liver-Specific PLIN2 Knockout Mice

Griffin

Bejarano

Wang

et al. 2021

Cells

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An imbalance in the storage and breakdown of hepatic lipid droplet (LD) triglyceride (TAG) leads to hepatic steatosis, a defining feature of non-alcoholic fatty liver disease (NAFLD). The two primary cellular pathways regulating hepatic TAG catabolism are lipolysis, initiated by adipose triglyceride lipase (ATGL), and lipophagy. Each of these processes requires access to the LD surface to initiate LD TAG catabolism. Ablation of perilipin 2 (PLIN2), the most abundant lipid droplet-associated protein in steatotic liver, protects mice from diet-induced NAFLD. However, the mechanisms underlaying this protection are unclear. We tested the contributions of ATGL and lipophagy mediated lipolysis to reduced hepatic TAG in mice with liver-specific PLIN2 deficiency (PLIN2LKO) fed a Western-type diet for 12 weeks. We observed enhanced autophagy in the absence of PLIN2, as determined by ex vivo p62 flux, as well as increased p62- and LC3-positive autophagic vesicles in PLIN2LKO livers and isolated primary hepatocytes. Increased levels of autophagy correlated with significant increases in cellular fatty acid (FA) oxidation in PLIN2LKO hepatocytes. We observed that inhibition of either autophagy or ATGL blunted the increased FA oxidation in PLIN2LKO hepatocytes. Additionally, combined inhibition of ATGL and autophagy reduced FA oxidation to the same extent as treatment with either inhibitor alone. In sum, these studies show that protection against NAFLD in the absence of hepatic PLIN2 is driven by the integrated actions of both ATGL and lipophagy.

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“…Furthermore, in animal models of NASH, a parallel time-dependent increase in LD size in hepatocytes and deposition of hepatic fibrosis has been demonstrated by automated computerized image analysis [ 8 ]. Finally, a parallel reduction in lipid droplet size and fibrosis was described in a liver-specific knockout mouse model for perilipin 2, an LD coating protein that inhibits lipolysis and regulates LD size, under a steatogenic diet [ 9 , 10 ].…”

Section: Discussionmentioning

confidence: 99%

“…Several experimental data have linked a greater size of LDs in hepatocytes and an increase in their size over time to the severity of liver fibrosis in NAFLD models [ 6 , 7 , 8 , 9 , 10 ]. In humans, hepatic fibrosis in NAFLD/NASH has been associated with the severity of macrovesicular steatosis [ 11 ] and the presence of true microvesicular steatosis [ 12 ].…”

Section: Introductionmentioning

confidence: 99%

“…In experimental models of NAFLD, cholesterol is more associated with large than small LDs in hepatocytes [ 15 , 16 ]. The size of LDs after their formation depends on very complex mechanisms including their catabolism through lipolysis and different types of lipophagy, their eventual fusion and, probably, also lipid synthesis on their surface [ 10 , 17 , 18 , 19 , 20 ]. Patatin-like phospholipase domain protein 3 (PNPLA3) is one lipolytic enzyme in hepatocytes located on large lipid droplets and several studies have shown that the PNPLA3 rs738409 (I148M) variant is powerfully linked to hepatic damage in NAFLD, at different levels such as steatosis, necroinflammation and fibrosis [ 21 , 22 ].…”

Section: Introductionmentioning

confidence: 99%

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The Propensity of the Human Liver to Form Large Lipid Droplets Is Associated with PNPLA3 Polymorphism, Reduced INSIG1 and NPC1L1 Expression and Increased Fibrogenetic Capacity

Ferri

Carotti

Carpino

et al. 2021

IJMS

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In nonalcoholic steatohepatitis animal models, an increased lipid droplet size in hepatocytes is associated with fibrogenesis. Hepatocytes with large droplet (Ld-MaS) or small droplet (Sd-MaS) macrovesicular steatosis may coexist in the human liver, but the factors associated with the predominance of one type over the other, including hepatic fibrogenic capacity, are unknown. In pre-ischemic liver biopsies from 225 consecutive liver transplant donors, we retrospectively counted hepatocytes with Ld-MaS and Sd-MaS and defined the predominant type of steatosis as involving ≥50% of steatotic hepatocytes. We analyzed a donor Patatin-like phospholipase domain-containing protein 3 (PNPLA3) rs738409 polymorphism, hepatic expression of proteins involved in lipid metabolism by RT-PCR, hepatic stellate cell (HSC) activation by α-SMA immunohistochemistry and, one year after transplantation, histological progression of fibrosis due to Hepatitis C Virus (HCV) recurrence. Seventy-four livers had no steatosis, and there were 98 and 53 with predominant Ld-MaS and Sd-MaS, respectively. In linear regression models, adjusted for many donor variables, the percentage of steatotic hepatocytes affected by Ld-MaS was inversely associated with hepatic expression of Insulin Induced Gene 1 (INSIG-1) and Niemann-Pick C1-Like 1 gene (NPC1L1) and directly with donor PNPLA3 variant M, HSC activation and progression of post-transplant fibrosis. In humans, Ld-MaS formation by hepatocytes is associated with abnormal PNPLA3-mediated lipolysis, downregulation of both the intracellular cholesterol sensor and cholesterol reabsorption from bile and increased hepatic fibrogenesis.

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Hepatic lipid droplets: A balancing act between energy storage and metabolic dysfunction in NAFLD

Cited by 141 publications

References 243 publications

Consumption of barley ameliorates the diabetic steatohepatitis and reduces the high transforming growth factor β expression in mice grown in α-minimum essential medium in vitro as embryos

Consumption of barley ameliorates the diabetic steatohepatitis and reduces the high transforming growth factor β expression in mice grown in α-minimum essential medium in vitro as embryos

Integrated Action of Autophagy and Adipose Tissue Triglyceride Lipase Ameliorates Diet-Induced Hepatic Steatosis in Liver-Specific PLIN2 Knockout Mice

The Propensity of the Human Liver to Form Large Lipid Droplets Is Associated with PNPLA3 Polymorphism, Reduced INSIG1 and NPC1L1 Expression and Increased Fibrogenetic Capacity

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