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Ballestri et al. Metab Target Organ Damage 2023;3:1 https://dx.doi.org/10.20517/mtod.2022.23 Page 3 of 22

result in a net imbalance between increased ECM synthesis on the one hand and ECM degradation on the
[15]
other, which results in hepatic fibrosis .
Several systemic signals from extra-hepatic tissues promote pro-fibrogenic responses in the liver, directly or
[15]
indirectly acting on hepatic stellate cells (HSCs) . For example, endotoxin, gut-derived pathogen-
associated molecular patterns, and danger-associated molecular patterns are fibrogenic by signaling through
[6]
TLR4 and other innate immune receptors . This finding implies that the gut is a significant driver of NASH
fibrosis through the microbiome’s effect and its interaction with the gut-liver axis, although the relative
[6]
contributions of liver-derived and systemic molecules remain uncertain .
Morphologic patterns of fibrosis progression differ according to the etiology of liver disease, and, in NASH,
fibrogenesis begins with the capillarization of sinusoids in zone 3 that progressively becomes panlobular
[3]
(so-called “pericentral fibrosis”) . NASH-specific fibrogenic pathways are increasingly being identified.
Because metabolic stress induces the synthesis and release of pro-inflammatory chemokines, Kupffer cells
gain inflammatory phenotypes contributing to the activation of HSC in concert with reactive oxygen
species, apoptotic signals, and endoplasmic reticulum stress . These pro-fibrogenic signals include
[16]
oxidized phospholipids and enhanced signaling by the intra-hepatocytic transcriptional activator TAZ,
which promotes paracrine fibrogenic signaling to HSCs via the secretion of Indian hedgehog ligand. The
PNPLA3-I148M variant’s effects on HSC fibrogenesis increase ECM and collagen deposition, resulting in
liver fibrosis .
[6]

Attesting to the biological complexity of fibrogenesis (which recruits different physiological pathways), the
coagulation system is also involved, as initially reported by the pathologist Wanless (recently reviewed) [17-19] .
This notion paves the way for anticoagulation strategies for treating NAFLD .
[18]

The cell type responsible for hepatic fibrogenesis is the peri-sinusoidal resident HSC, which is activated to
gain a myofibroblast phenotype . Therefore, all factors regulating the individual steps from HSC activation,
[6]
[15]
proliferation, function, and survival represent essential therapeutic targets . Additional therapeutic options
include the elimination of the hepatotoxic agent(s) and (importantly) degradation of excessive ECM
deposition . Innovative approaches include manipulation of the coagulation cascade, anti-platelet drugs,
[15]
and targeting integrins, which are master regulators of transforming growth factor-β activity [18,20-22] . Finally,
[23]
cell therapy approaches are also under investigation .

Collectively, management approaches support the relatively recent notion that the complex fibrogenic
process is not irreversible, offering a chance for the prevention and therapy of fibrosis [3,24,25] .

The demonstration that, by treating liver fibrosis, we also address CVD would represent strong proof-of-
concept evidence for a causal association between advanced liver disease and major cardiovascular events
(MACE). However, rather than an improbable silver bullet, the reversal of liver fibrosis presently requests a
holistic approach ranging from lifestyle changes to surgery [25,26] . Halfway between diet, exercise, and weight
loss on the one end and bariatric surgery on the other end, there could be a pharmacological approach to
treating fibrosis associated with NASH. This topic (beyond the scope of the present review) has been
covered by Friedman et al. . Among the various possible strategies, we highlight the study by Yang et
[6]
al., who fed a choline-deficient amino acid diet to rats and found that histological features of NASH
and fibrosis were significantly attenuated by treatment with 4-methylumbelliferone, an inhibitor of
hyaluran synthesis (200 mg/kg/day) for the final two weeks of the altered diet . The actual relevance
[27]
of these findings to human NASH remains to be demonstrated. However, conflicting with the widely
appreciated role of plasma